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Cent. Eur. J. Biol. • 8(10) • 2013 • 943-957 DOI: 10.2478/s11535-013-0209-6

Central European Journal of Biology

New perspectives on antibacterial drug research

Review Article

Joanna Ziemska, Aleksandra Rajnisz, Jolanta Solecka*

Laboratory of Biologically Active Compounds, National Institute of Public Health - National Institute of Hygiene, 00-791 Warsaw, Poland

Received 14 March 2013; Accepted 10 May 2013

Abstract: Bacterial resistance to commonly used is constantly increasing. particularly dangerous for human life are -resistant , -resistant Enterococcus faecium and fluoroquinolone-resistant . Hence, there is an incessant need for developing compounds with new modes of action and seeking alternate drug targets. In this review, the authors discuss the current situation of antibacterial medicines and present data on new targets. Moreover, alternatives to antibiotics, such as bacteriophages, antimicrobial peptides and monoclonal antibodies, are presented. The authors also draw attention to the valuable features of natural sources in developing antibacterial compounds. The need to prevent and control infections as well as the reasonable use of currently available antibiotics is also emphasized. Keywords: Bacterial resistance • Antibacterial compound • Drug discovery • Target • Antimicrobial peptides © Versita Sp. z o.o.

1. Introduction pathogens (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa) [2]. The use of antibiotics, especially the excessive and In this review, the authors will discuss the present indiscriminative use, both in medicine and veterinary status of bacterial resistance to antibiotics, especially science has contributed to the emergence of drug of bacterial species that cause serious hospital and resistant organisms. Antimicrobial drug resistance community-acquired infections. Furthermore, the constitutes a growing problem worldwide [1]. Infections review presents antibiotics that are currently on the caused by resistant pathogens result in increased market and summarizes novel promising discoveries in mortality and morbidity among human and animal drug development. The authors will also refer to new populations. In addition, pathogenic microorganisms, antibacterial targets and other alternatives to antibiotics. including Staphylococcus aureus, and Clostridium difficile, contribute to many hospital-acquired infections. Gram-negative 2. How antibiotics became outdated? bacteria are traditionally more difficult to destroy than Gram-positive bacteria as they contain an The lack of new and effective antibacterial compounds outer membrane that constitutes an extra barrier for is due to several factors. First of all, it is difficult to find antibacterial compounds. The latest reports from the new antibacterial compounds with good pharmacological American and European disease associations claim profiles and low toxicity for the host. Furthermore, from that there are only a few antibiotics in the clinical an economic point of view, pharmaceutical companies pipeline that are more effective in targeting Gram- are more interested in developing drugs for chronic negative bacteria than existing pharmaceuticals conditions than for short-term treatments. Moreover, it on the market [1]. In the surveillance report titled is preferable when antibiotics target multiple species. “ surveillance in Europe” made In addition, bacteria tend to develop resistance to by the European Centre for Disease Prevention and antimicrobials which restricts their use and consequently Control, the authors show a general, Europe-wide causes drug sales decline [3]. Finally, the chemical increase in antimicrobial resistance in Gram-negative structures of antibiotics, especially those derived from

* E-mail: [email protected] 943 New perspectives on antibacterial drug research

nature, are complex. They consist of many stereocenters, 3. Present state of antibacterials rotatable bonds, proton donors and acceptors. Therefore, the discovery, design and development of novel, efficient The majority of antibiotics currently applied in medical drugs is more demanding [4,5]. therapy belong to drug classes discovered before Antibiotics are one of the most efficient compounds 1970, during the “golden age” of drug discovery. Since used in fighting human diseases. However, bacterial that time, most accomplishments in drug development resistance to known antibiotics is growing and has were based on improvements and modifications to become a serious limitation in the treatment of patients already existing compounds, giving rise to more potent worldwide. Antibiotic resistance has essentially analogues with greater stability to bacterial resistance developed by two main processes: mutation and [3]. Currently, nearly all anti-Gram-positive compounds acquisition of resistance genes by horizontal gene under development, or recently introduced on the transfer (HGT). There are at least four types of market, are analogues of already existing molecules, identified resistance mechanisms: alteration of the especially certain β-lactams, like (e.g. antibiotic, alteration of the target, drug efflux or reduced and ceftaroline) and quinolones, which permeability of the [6]. were modified to target MRSA and are discussed below A major infectious problem in hospitals due to (i) [11]. resistance to known antibiotics, (ii) virulence of some Since 2000, more than 20 antibacterial compounds bacterial species, or (iii) high rate of recurrence, is have been introduced to the market. Some of them constituted by the “ESCAPE” pathogens, which include derive from natural products and usually carry semi- Enterococcus faecium (vancomycin-resistant), S. synthetic modifications, e.g. (2003), aureus (methicillin-resistant), C. difficile, Acinetobacter (2004), (2005), retapamulin baumannii, Pseudomonas aeruginosa (fluoroquinolone- (2007), ceftobiprole medocaril (2008), ceftaroline resistant) and Enterobacteriaceae species [7]. The fosamil (2010), (2009), (2011), abbreviation “ESCAPE” was proposed by Peterson in (2002), (2002), (2005) 2009 to replace the previous “ESKAPE” which included and pivoxil (2009). Others are of synthetic E. faecium, S. aureus, Klebsiella pneumoniae, A. origin and usually belong to fluoroquinolones, e.g. baumannii, P. aeruginosa and Enterobacter species (2002), (2002), (offered by Rice in 2008, [8]). The change of abbreviation (2002), mesylate (2004), (“ESKAPE”) was related to increasing importance and (2007), (2008), (2009), threat of other bacterial species. Master et al. reported antofloxacin (2009), oxazolidinones (, 2000) on changing antimicrobial resistance in the United [www.fda.gov, 1, 12-14] (Table 1). States between 2007-2011, using the Surveillance Antibacterial compounds that are currently Network (TSN) database. They mostly focused on undergoing pre-clinical and clinical development (phase bacterial resistance to β-lactams. The authors showed I, II, III) are listed in Table 2. Newly designed, modified that the bacteria tested (S. aureus, E. faecalis, E. drugs, which have already been introduced on the faecium, E.coli, K. pneumoniae, Enterobacter spp., market, as well as those undergoing clinical trials and P. aeruginosa, A. baumannii) have various different their modes of action are presented below in detail. mechanisms of resistance that impact the activity of β-lactam antibiotics. The level of A. baumannii resistance 3.1 Cephalosporins to increased from 23.9% to 34.3% during the Ceftobiprole, a new , is active against period from 2007 to 2011. K. pneumoniae resistance to MRSA and -resistant streptococci [14]. This imipenem also grew, while methicillin-resistant S. aureus drug was first introduced in 2008 in Switzerland and (MRSA) rates decreased during 2007-2011. About half Canada, later withdrawn (in 2010), and is currently of S. aureus species detected in 2011 were resistant in clinical trials (Basilea Pharmaceutica Ltd.) to methicillin [9]. The spread of bacteria resistant [www.clinicaltrials.gov, 13]. Ceftaroline, on the to , for example Enterobacteriaceae other hand, was approved by the U.S. Food and members, constitutes a serious threat due to the fact Drug Administration (FDA) for treatment of acute that carbapenems are broad-spectrum antibiotics and bacterial skin and skin structure infections (SSSI) and often are the only antibacterials effective against difficult- community-acquired pneumonia (CAP) [15]. It is a to-treat infections that are incurable by other antibiotics broad spectrum antibiotic with activity against MRSA [10]. The current situation on antibacterial market is still and drug resistant S. pneumoniae [16]. uncertain because many therapeutic options for the CXA-101 is a novel cephalosporin- ceftolozane, treatment of infections are becoming limited [7]. which displays potent activity against P. aeruginosa

944 J. Ziemska et al.

Drug name Drug class Target Year introduced

Natural origin

daptomycin lipopeptide bacterial cell membrane 2003

telithromycin protein synthesis 2001 Europe, 2004 FDA [38]

tigecycline protein synthesis 2005 [34]

retapamulin protein synthesis 2007

ceftobiprole medocaril cephalosporin bacterial cell wall 2008

cephalosporin bacterial cell wall 2010 [15,16]

telavancin bacterial cell wall 2009 [36]

fidaxomicin 18-membered macrocycle RNA polymerase inhibitor 2011 [59]

biapenem bacterial cell wall 2002, Japan [15]

ertapenem carbapenem bacterial cell wall 2002, Europe [25,26]

doripenem carbapenem bacterial cell wall 2005, Japan, [20]

tebipenem pivoxil carbapenem bacterial cell wall 2009, Japan [22,23]

Synthetic origin

prulifloxacin fluoroquinolone gyrase/topoisomerase IV 2002

pazufloxacin fluoroquinolone gyrase/topoisomerase IV 2002

balofloxacin fluoroquinolone gyrase/topoisomerase IV 2002

gemifloxacin mesylate fluoroquinolone gyrase/topoisomerase IV 2004

garenoxacin fluoroquinolone gyrase/topoisomerase IV 2007

sitafloxacin fluoroquinolone gyrase/topoisomerase IV 2008

besifloxacin fluoroquinolone gyrase/topoisomerase IV 2009

antofloxacin fluoroquinolone gyrase/topoisomerase IV 2009

linezolid oxazolidinone protein synthesis 2000

Table 1. Drugs introduced to the market since 2000 [1,12-14, ww.fda.gov].

and appears to be stable against bacterial resistance TD-1792 causes bacterial susceptibility and probably mechanisms. Data shows that it can be a potent agent will result in slower development of resistance [19]. in the treatment of chronic respiratory infection caused by P. aeruginosa in cystic fibrosis [17]. CXA-201 (Cubist 3.2 Carbapenems Pharmaceuticals) is a combination of ceftolozane and Carbapenems can be divided into those that are a β-lactamase inhibitor, , that is currently in active against P. aeruginosa (biapenem, doripenem, phase 3 clinical trials for the treatment of complicated , ) and those that are not urinary tract infections (cUTI) and complicated intra- (ertapenem, tebipenem pivoxil, ME1036). Biapenem abdominal infections (cIAI). It is active against Gram- was approved for use in Japan in 2002 and has a broad negative bacteria, including multidrug-resistant (MDR) spectrum of activity against S. pneumoniae, MSSA, P. aeruginosa [www.clinicaltrials.gov, 18]. A. baumannii, ESBL-producing Enterobacteriaceae TD-1792, a multivalent glycopeptide-cephalosporin and moderate activity against P. aeruginosa [13,15]. antibiotic, which combines the activities of a glycopeptide Doripenem is active in vitro against streptococci, MSSA, and β-lactam, is currently in clinical development ESBL-producing Enterobacteriaceae, Acinetobacter (completed phase II, Theravance) [www.clinicaltrials.gov]. spp. and Bacteroides fragilis. In comparison to another The major application of TD-1792 is in treatment of carbapenem (meropenem), doripenem is also more cSSSI [12]. It possesses potent activity against Gram- effective against P. aeruginosa [20]. Razupenem positive bacteria, including methicillin-sensitive S. is also a novel 1β-methylcarbapenem which acts aureus (MSSA), MRSA and vancomycin-intermediate against MDR Gram-positive and Gram-negative S. aureus (VISA). The unique chemical structure of bacteria, especially MRSA and vancomycin-resistant

945 New perspectives on antibacterial drug research

Drug candidate Drug class Target (Pre-)cliniacal phase

In pre-clinical development

Amixicile nitrothiazolide TPP inhibitor Pre-clinical [62]

MX-2401 lipopeptide bacterial cell wall Pre-clinical, BioWest Therapeutics [35] DNA gyrase / Pre-clinical, Achillion Pharmaceuticals ACH-702 isothiazoloquinolone topoisomerase IV [54] RX-P763, RX-P766, RX-P770, pyrrolo[2,3-d]pyrimidin-2-ones protein synthesis Pre-clinical, RibX Pharmaceuticals [56] RX-P792, RX-P793, RX-P808

In phase I Phase I, Basilea Pharmaceutica Ltd BAL30072 bacterial cell wall [27,28] (NXL104)+ β-lactamase + bacterial β-lactam inhibitor + cephalosporin Phase I, Cerexa/Forest Laboratories ceftaroline fosamil cell wall ACHN-975 - LpxC Phase I completed, Achaogen

In phase II

TD-1792 glycopeptide-cephalosporin bacterial cell wall Phase II completed, Theravance [19] β-lactamase inhibitor + β-lactamase + MK-7655 +Imipenem/cilastatin Phase II, Merck [32] carbapenem bacterial cell wall (RX-1741) oxazolidinone protein synthesis Phase II, RibX Pharmaceuticals [45]

BC-3781 pleuromutilin protein synthesis Phase II, Nabriva Therapeutics [58]

LFF571 thiopeptide - Novartis

Plazomicin (ACHN-490), protein synthesis Phase II completed, Achaogen DNA gyrase/ Phase II completed, Rib-X (RX-3341) fluoroquinolone topoisomerase IV Pharmaceuticals [46] DNA gyrase/ Phase II completed, Furiex JNJ-Q2 fluoroquinolone topoisomerase IV Pharmaceuticals, [48] NXL-103 protein synthesis Phase II completed [57] (E)-N-methyl-N-((3-methylbenzofuran- 2-yl)methyl)-3-(7-oxo-5,6,7,8- Phase II completed, Affinium AFN-1252 fatty acid synthesis tetrahydro-1,8-naphthyridin-3-yl) Pharmaceuticals acrylamide KB001-A monoclonal antibody - Phase II, KaloBios Pharmaceuticals [11]

In phase III Phase III trial terminated, Paratek (PTK 0796) aminomethylcycline protein synthesis Pharmaceuticals [33] Phase III completed, Durata Therapeutics lipoglycopeptide bacterial cell wall [37] Phase III completed, Advanced Life ketolide protein synthesis Sciences [41] Phase III oral form, Cempra (CEM-101) fluoroketolide protein synthesis Pharmaceuticals [42] bacterial cell wall + CXA-201 cephalosporin/β-lactamase inhibitor Phase III, Cubist Pharmaceuticals [18] β-lactamase Phase III completed, Trius Therapeutics (TR-701, torezolid) oxazolidinone protein synthesis [14,45] membrane Surotomycin lipopeptide Phase III, Cubist Pharmaceuticals [60] depolarization avibactam β-lactamase + bacterial β-lactamase inhibitor+ cephalosporin Phase III, Astra Zeneca [31] (NXL104)+ cell wall toxin A and B MK-3415A and MK-6072 monoclonal antibodies Phase III, Merck [91] (Clostridium difficile) DNA gyrase/ PD 0305970 and PD 0326448 quinazolinediones Pfizer [50] topoisomerase IV

Table 2. Newly discovered compounds in the clinical pipeline [www.clinicaltrials.gov].

946 J. Ziemska et al.

Enterococcus (VRE), and may be a promising Other non-β-lactam inhibitors of β-lactamases have candidate for the treatment of nosocomial infections. been identified, e.g. avibactam (NXL104, Novexel/ It has lower activity against P. aeruginosa than AstraZeneca) and MK-7655 (Merck). These related comparable carbapenems (imipenem, meropenem) molecules (with diazabicyclo structures) inhibit class [21]. Tebipenem pivoxil is a whose active A and class C enzymes, including extended-spectrum metabolite was shown to kill various groups of bacteria, and KPC-type β-lactamases [3]. Moreover, avibactam including penicillin-nonsusceptible S. pneumoniae. It in combination with ceftazidime displays in vitro shows potent activity against pathogens causing UTI antibacterial activity against P. aeruginosa isolates and respiratory tract infections. This oral carbapenem [31]. Cerexa is currently recruiting participants for may be a potential drug for treatment of persistent phase I clinical trials of avibactam in combination with otitis media, upper respiratory infection and bacterial ceftaroline fosamil (www.clinicaltrials.gov). MK-7655 pneumonia in pediatric patients [22,23]. ME1036 is was combined with imipenem and tested against carbapenem drug with strong antibacterial activity imipenem-resistant Gram-negative isolates in vitro. against penicillin-resistant S. pneumoniae, E. faecalis, The MICs for the strains were reduced, suggesting Haemophilus influenzae and Enterobacteriaceae a potent efficacy of these drugs in combination strains but is not active against P. aeruginosa isolates [www.clinicaltrials.gov, 32]. Both of the compounds [12,15,24]. Finally, ertapenem, was approved by the seem to be a solution for carbapenem usage, due to their FDA for treatment of IAI, cSSSI, cUTI, acute pelvic inhibition of β-lactamases, which destroy β-lactams. infections and CAP [25,26]. 3.5 3.3 There are also some “next-generation” aminoglycosides BAL30072 (Basilea Pharmaceutica Ltd.) is a new in clinical development, e.g. . Plazomicin monobactam. MDR P. aeruginosa, Acinetobacter spp. (ACHN-490, Achaogen) in 2012 completed phase isolates, as well as other Gram-negative nonfermenters 2 clinical trials for the treatment of cUTI and acute (e.g. Burkholderia spp. and Stenotrophomonas pyelonephritis. Phase 1 studies carried earlier were maltophilia), are susceptible to this β-lactam. It inhibits aimed to determine drug safety, blood , bifunctional penicillin-binding proteins PBP 1a and PBP and lung penetration as well as to evaluate the effect of 1b and possesses high affinity for PBP 3. Furthermore, plazomicin administered intravenously on the QT/QTc Page et al. showed that BAL30072 is active against 70% interval in healthy volunteers (www.clinicaltrials.gov). of the carbapenem-resistant Enterobacteriaceae strains tested, including strains producing carbapenemases 3.6 Aminomethylcyclines (class A, B and D) [27]. Therefore, this compound Omadacycline (PTK0796, Paratek Pharmaceuticals) is may be complementary to carbapenems. In a study a new -derived broad-spectrum antibiotic for by Hofer et al., BAL30072 was combined with different treatment of complicated bacterial SSSI. It’s chemical carbapenems and synergistic antibacterial activity structure is based on . Omadacycline was observed against many Enterobacteriaceae and exhibits activity against both Gram-positive (MSSA and P. aeruginosa [28]. MRSA) and Gram-negative bacteria. It is also active against tetracycline-resistant pathogens. In phase 2 3.4 β-lactams with β-lactamase inhibitors study, the safety and tolerability profile of omadacycline Among the new MBL inhibitors currently under was comparable to that of linezolid. No drug-related investigation are BAL30376 and ME1071. The first serious side-effects were noted [33]. Unfortunately compound consists of two monobactam moieties and phase 3 clinical trials on omadacycline was terminated . It is active against metallo-β-lactamase in 2013 (www.clinicaltrials.gov). (MBL)-producing strains and isolates of Burkholderia cepacia and carbapenemase-producing A. baumannii, 3.7 but KPC-producing strains are resistant [15,29]. Tigecycline, a member of the glycylcyclines and The second, ME1071, is a maleic acid derivative, approved by the FDA in 2005, was developed to non-β-lactam inhibitor, used in combination with overcome the difficulties with resistance to β-lactams. It potentiates the activity of ceftazidime and (mainly ribosomal protection and drug efflux). It was carbapenems against MBL-producing P. aeruginosa approved for treatment of cSSSI, cIAI and CAP. It and significantly lowers the MIC of biapenem ina shows a broad spectrum of antimicrobial activity against concentration-dependent manner against MBL- MRSA, VRE and other MDR Gram-negative bacteria producing P. aeruginosa [25,30]. [www.fda.gov, 14,34].

947 New perspectives on antibacterial drug research

3.8 Lipopeptides [42]. This fluoroketolide is active against Neisseria MX-2401 is a new semi-synthetic calcium (Ca2+)- gonorrhoeae isolates and its use in uncomplicated dependent lipopeptide antibiotic in pre-clinical gonorrhea is also being studied in clinical trials (phase I) development. It is active against various Gram-positive [www.clinicaltrials.gov, 43]. bacteria, including strains not susceptible to vancomycin, , penicillin, methicillin, and 3.11 Oxazolidinones others. Interestingly, it possesses a different mode of Oxazolidinones (linezolid), a new class of antibiotics, action than daptomycin, the first calcium-dependent which exhibit structures different from old, known drugs, lipopeptide drug compound developed. Its mechanism were expected to bypass many resistance mechanisms of action relies on inhibition of synthesis that normally affect antibiotic activity. Linezolid has

by binding to a specific substrate (C55-P) involved in been on the market since 2000 as a drug active against several biosynthetic pathways. This interaction causes MRSA and VRE strains. However, resistance to linezolid inhibition of the cell wall precursor lipids I, II and the wall occurred very quickly in the presence of the cfr gene. Cfr teichoic acid precursor, lipid III [35]. is responsible for resistance to phenicols, , oxazolidinones, and streptogramin A [44]. 3.9 As a consequence new members of the oxazolidinones Among the recently introduced antibacterial compounds are being extensively studied, including radezolid is telavancin (trade name Vabativ®, Theravance, 2009). (RX-1741, Rib X Pharmaceuticals), and tedizolid It is a lipoglycopeptide that exhibits dual mechanisms phosphate (TR-701, torezolid, Trius Therapeutics). of action based on inhibition of bacterial peptidoglycan Radezolid is in phase 2 clinical trials on patients with synthesis at the transglycosylase step and membrane uncomplicated SSSI (www.clinicaltrials.gov). Tedizolid depolarization [12,13,36]. Another lipoglycopeptide, phosphate, a prodrug of tedizolid is in phase 3 clinical trials dalbavancin (a second generation, semi-synthetic for treatment of SSSI and was determined to be 4 to 8-fold compound), is currently in clinical trials by Durata more active than linezolid against linezolid-susceptible and Therapeutics for intravenous administration to patients resistant staphylococcal and enterococcal strains [14,45]. with acute bacterial SSSI caused by Gram-positive bacteria [www.clinicaltrials.gov]. The advantage of 3.12 Fluoroquinolones and compounds with dalbavancin is its very long half-life (ranging from 149 to anti-gyrase/topoisomerase activity 250 h), which allows it to be administered once a week Another important group of antibacterials are the [37]. fluoroquinolones, which, as mentioned earlier, comprise mostly synthetic compounds. The list of 3.10 the approved fluoroquinolones is included in Table 1. Telithromycin ketolide is an -derivative Delafloxacin (RX-3341, Rib-X Pharmaceuticals) is a approved by the FDA in 2004 for CAP, acute bacterial member of the fluoroquinolones, which completed exacerbations of chronic bronchitis (ABECB) and acute phase 2 clinical trials for cSSSI and acute bacterial bacterial sinusitis [14,38, www.fda.gov]. It shows more SSSI (www.clinicaltrials.gov). It is significantly potent activity in vitro in studies against - more active than other quinolones against Gram- susceptible organisms than erythromycin. It also targets positive organisms [46, www.clinicaltrials.gov]. erythromycin-resistant pneumococci [39]. However, It shows potent in vitro activity against MRSA isolates after approval of telithromycin, its alarming adverse and the development of resistant mutants in MRSA events were noted, such as hepatotoxicity, myasthenia is minimized [47]. Another new compound is JNJ-Q2 gravis exacerbation and vision disturbances. Therefore, (Furiex Pharmaceuticals), fluorinated 4-quinolone. telithromycin was withdrawn for treating ABECB and It exhibited activity against S. pneumoniae and acute bacterial sinusitis [40]. Cethromycin (Advanced staphylococci, including MRSA and completed phase II Life Sciences), another ketolide agent, was shown to clinical trials for the treatment of SSSI [48]. target CAP while having a high safety profile. In a study There are also some pyrrolopyrimidine inhibitors of by English et al., the clinical efficacy and safety was the bacterial topoisomerases DNA gyrase (GyrB) and studied and confirmed in therapy of mild to moderate topoisomerase IV (ParE) under development (Trius CAP in adults. The authors conclude that cethromycin Therapeutics). This dual targeting strategy, inhibiting ATP- can be a potent solution for outpatient treatment of binding sites of both GyrB and ParE, seems to be a novel CAP [14,41]. A novel compound, solithromycin (CEM- mechanism of action. In a recent study by Trzoss et al. 101) is in the clinical pipeline (oral form in phase III, a series of pyrrolopyrimidine inhibitors was optimized Cempra Pharmaceuticals) for the treatment of CAP to exhibit antibacterial activity against Gram-negative

948 J. Ziemska et al.

pathogens, including P. aeruginosa, A. baumannii, E. coli MIC distributions. Their mode of action targets the large and potent activity against S. aureus [49]. subunit of the bacterial ribosome [56]. PD 0305970 and PD 0326448 (quinazoline-2,4-diones) are both GyrB/ParE inhibitors 3.14 which show activity against Gram-positive bacteria that Among drugs currently in clinical trials is NXL-103, a frequently carry quinolone resistance mutations [50]. semisynthetic streptogramin (combination of flopristin Pyrrolamides are novel DNA gyrase inhibitors. Recently, and linopristin), which can be used in the treatment Eakin et al. described initial prototypes of pyrrolamides of CAP and community-acquired or nosocomial with in vitro antibacterial activity against Gram-positive MRSA, VRE infections, and acute bacterial SSSI bacteria and selected Gram-negative pathogens. These [www.clinicaltrials.gov, 57]. NXL-103 was also shown compounds target the ATP-binding site of GyrB [51]. to have activity against S. aureus in a biofilm model. In another study a series of compounds based on Furthermore, in several in vitro assays it was up to four imidazopyridine and triazolopyridine scaffolds were times more active (lower MIC values) than quinupristin/ identified. They also act through inhibition of GyrB/ParE. dalfopristin, a parenterally administered streptogramin They present activity mostly against Gram-positive [57]. bacteria (MSSA, MRSA, S. pneumoniae) [52]. There is another group of compounds, heteroaryl 3.15 Pleuromutilins isothiazolones (HITZs), which display antibacterial activity In 2007, the FDA approved retapamulin, the first against Gram-positive bacteria, including MRSA. Their representative of a new class of antibacterials called mode of action also relies on inhibition of DNA gyrase pleuromutilins, for topical treatment of cSSSI. Retapamulin and topoisomerase IV. These compounds are superior is a 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)- to some of the fluoroquinolones, which are inactive sulfanyl-acetate (brand name Altabax®, GlaxoSmithKline) against MRSA carrying mutations in topoisomerases [53]. which targets the 50S subunit of bacterial ribosomes One of them, ACH-702 (isothiazoloquinolone, Achillion and is used for topical treatment of caused Pharmaceuticals) displayed potent activity against by susceptible strains of S. aureus and Streptococcus antibiotic-resistant Gram-positive bacteria (including MRSA) pyogenes [www.fda.gov]. Two additional pleuromutilin in vitro and in vivo. Furthermore, it is also active against antibiotics, BC-3781 and BC-3205, are being developed some Gram-negative bacteria (H. influenzae, Moraxella by Nabriva Therapeutics. Both of them demonstrate catarrhalis, and a Neisseria spp., with minor activity against potent antibacterial activity against S. aureus, including Enterobacteriaceae) [54]. NXL101 is another dual inhibitor MRSA, as well as against S. pneumoniae and H. of the essential bacterial DNA replication enzymes DNA influenzae. The former (BC-3781) is in phase II and gyrase and topoisomerase IV (Novexel). NXL101 is a is being developed for the systemic treatment of acute quinoline compound with antibacterial activity against Gram- bacterial SSSI and CAP [www.clinicaltrials.gov, 58]. positive bacteria, including methicillin and fluoroquinolone- resistant strains [55]. 3.16 Anti-C. difficile drugs All of the above described dual inhibitors of Pharmaceutical companies are also interested in DNA gyrase and topoisomerase are promising drug finding effective drugs against C. difficile, which is the candidates due to the fact that they are often active most common cause of health care-related infectious against fluoroquinolone-resistant strains and that diarrhea in developed countries. Novartis is developing resistance development to these compounds is unlikely a novel anti- C. difficile molecule, LFF571 and presently to proceed rapidly. the company is recruiting participants for phase II clinical trials [www.clinicaltrials.gov]. Fidaxomicin 3.13 Pyrimidin-2-ones (Dificid®), an RNA polymerase inhibitor developed by Rib-X Pharmaceuticals has a series of compounds in Optimer Pharmaceuticals and Cubist Pharmaceuticals, preclinical development called the RX-04 program. This was approved by the FDA (in 2011) for the treatment program is focused on the discovery of compounds with of C. difficile infections. It is a naturally occurring new modes of action. One group of compounds that 18-membered macrocycle with a narrow-spectrum have emerged from the RX-04 program are substituted profile shown to eradicate C. difficile selectively with pyrrolo[2,3-d]pyrimidin-2-ones (RX-P763, RX-P766, minimal disruption of the normal intestinal flora [59]. In RX-P770, RX-P792, RX-P793, RX-P808). Housman et addition, Cubist Pharmaceuticals is developing a novel al. demonstrated anti-P. aeruginosa activities of these oral lipopeptide, surotomycin (CB-315), active against compounds. Additionally, these compounds exhibited C. difficile-associated diarrhea, which is currently in activities against MDR pathogens and have narrow phase 3 clinical trials [www.clinicaltrials.gov, 60].

949 New perspectives on antibacterial drug research

Another novel drug active against C. difficile division in most bacteria [65]. After translational initiation, is nitazoxanide [2-acetyloxy-N-(5-nitro-2-thiazolyl) PDF catalyzes the hydrolytic removal of the N-terminal benzamide]. It is a nitrothiazolide that possesses a broad formyl group from nascent proteins, which are further spectrum of activity against anaerobic bacteria and processed along bacterial protein synthesis pathways. parasites. It was approved by the FDA as an antiparasitic Actinonin and a novel compound, BB-3497, are both compound (brand name Alinia®, Romark Laboratories) potent inhibitors of E. coli PDF [68]. FtsZ, a homolog against Giardia intestinalis and Cryptosporidium parvum of eukaryotic tubulin, has significant importance for in adults and children. Data have shown that the drug bacterial cell replication [69]. is also active against viruses [14,61]. Amixicile is a Lipid II is the antibacterial target of a number of propylamine derivative of nitazoxanide with better drugs, including vancomycin, mannopeptimycins and solubility in water and efficacy against C. difficile in plectasin. Mannopeptimycins inhibit peptidoglycan mouse infection models. Independent investigations synthesis at the transglycosylation level by targeting the have determined that nitazoxanide and amixicile are membrane-bound precursor lipid II. They show activity inhibitors of thiamine pyrophosphate (TPP) which is a against MRSA, penicillin-resistant streptococci and vitamin cofactor of pyruvate: ferrodoxin oxidoreductase moderate activity against VRE. Plectasin also binds to (PFOR). Interestingly, by inhibiting vitamin cofactor, and lipid II but possesses a rather low level of activity against not the enzyme per se, these nitrothiazolides may avoid staphylococci [4,70]. fast-developing resistance [62]. Homoserine transacetylase (HTA) plays an important role in the biosynthesis of methionine in various microorganisms (Gram-positive and Gram- 4. New targets negative bacteria and many fungi) and is essential for growth in Met-poor environments. The absence of this The goal of many scientists working on developing new enzyme in humans makes it an attractive target for antibacterial agents is discovering and designing drugs new antimicrobial agents. Recently, β-lactone natural acting via novel mechanisms of action and directed products inhibiting HTA were described [71]. against novel targets [63]. Recognized antibiotic targets Among the new classes of antimicrobials are include: cell wall biosynthesis, lytic enzymes, fatty acid compounds interacting with bacterial DNA. Bis-indole biosynthesis, folic acid biosynthesis and cell division antibiotics, such as MBX1162, inhibit DNA and RNA [64]. The majority of antibacterial compounds impair synthesis. Data showed that MBX1162 is potent these processes or enzymes. Yet, it is highly possible in vitro against MDR A. baumannii, ESBL-producing K. that there are many more enzymes and/or structures pneumoniae, VRE and MRSA [15,72]. However, these in the bacterial cell that could constitute targets for types of compounds are usually highly cytotoxic to antibacterial drug activity. mammalian DNA, which may limit their usage. Antibacterial targets can generally be defined as A novel bacterial target is the E. coli primase enzyme. bacteria enzymes that are essential for cell function but Bacterial primases are essential for DNA replication. at the same time are distinct from related mammalian Agarwal et al. identified compounds that exhibit primase structures. Among the newly discovered targets is the inhibition in vitro and antibacterial activity [73]. histidine kinase/response regulator pair WalK/WalR. Prokaryotic zinc metalloproteins, such as carbonic This two-component system is highly conserved and anhydrase and histidinol dehydrogenase, have recently essential for low G + C Gram-positive bacteria (e.g. S. been taken into consideration as anti-Brucella targets. aureus, Bacillus subtilis and E. faecalis [65,66]), where They are required for growth and/or virulence in several it is necessary for bacterial cell wall metabolism and intracellular pathogenic species. Selective inhibitors of growth. Signermycin B was found to be an inhibitor of these bacterial enzymes are regarded as one potential the histidine kinase WalK [67]. new anti-Brucella therapy [74]. Another prospective target, UDP-3-O-acyl-N- β-ketoacyl synthases I/II (Fab F/B), key enzymes in acetylglucosamine deacetylase (LpxC), is an enzyme the production of bacterial cell membrane fatty acids, are involved in lipopolysaccharide biosynthesis (lipid A) yet another example of antibacterial targets. A compound in Gram-negative bacterial cells [15]. The Achaogen recently discovered by Merck, platensimycin, exhibits company has developed an LpxC inhibitor, ACHN-975. activity against Gram-positive bacteria and was shown to It is in phase 1 clinical trials for the treatment of MDR be a Fab F/B inhibitor [11,75]. Another compound which Pseudomonas spp. [www.clinicaltrials.gov]. inhibits fatty acid synthesis (Fabl inhibitor) is AFN-1252 Other potential targets for new antibacterials are (previously named API-1252, Affinium Pharmaceuticals), peptide deformylase (PDF) and FtsZ, required for cell (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-

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3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl) membrane, resulting in leakage of the cell contents acrylamide. It is currently under phase 2 clinical trials into the extracellular medium. Histatins possess potent in oral form for treatment of acute bacterial SSSI antifungal properties and some antibacterial activities caused by staphylococci. Data shows that it is active [82,84-86]. Antimicrobial peptides show promising in vitro against MSSA, community acquired-MRSA, and antibacterial activities in vitro, however challenges hospital acquired-MRSA [www.clinicaltrials.gov, 76]. remain regarding their in vivo application (including delivery form, toxicity, high cost of production and allergic side effects [87]). 5. Alternatives to antibiotics Bacteriocins are a group of AMPs produced by bacteria. They differ from antibiotics in several aspects. Innovative antibiotic substitutes, like bacteriophages They are produced on the surface of ribosomes in (phages), antimicrobial peptides (AMPs) and microbial cells, while antibiotics are primarily secondary monoclonal antibodies, have also been described. metabolites of the cell. Moreover, bacteriocins do not Clinical evidence shows that phages can be successfully accumulate in tissues and can be effective against applied in the treatment of infections caused by Gram- antibiotic-resistant pathogens [88,89]. However, positive and Gram-negative bacteria. Bacteriophages bacteriocins do not have as broad a spectrum of have been used in medicine since the beginning of antibacterial activity as antibiotics. Among the newly the 20th century [77,78]. Their advantage is that they described bacteriocins is L-1077, produced by are high specific to a target bacterium and therefore Lactobacillus salivarius L-1077. MICs of this peptide will not affect the microbial flora of humans. Moreover, determined against 33 Gram-negative and Gram- bacteriophages are harmless to human and animal cells positive bacterial isolates ranged from 0.09 to 1.5 µg/ml [79]. One disadvantage to the use of bacteriophages [88]. is that massive bacterial lysis may lead to toxic shock. Human is a pivotal component of the Moreover, systemic use of phages for treating patients innate immune system and can be applied as an is likely to be immunogenic and may induce neutralizing antimicrobial peptide agent. It acts against both antibodies. Apart from human therapy, bacteriophages Gram-negative and Gram-positive bacteria, but is less have also been evaluated for use in the poultry and effective against the former due to the presence of an cattle industries, aquaculture and sewage treatment outer membrane in these bacteria. Human lysozyme [80,81]. does not effectively eradicate bacteria during chronic AMPs are produced in different tissues by plants, conditions. Yet, application of recombinant forms of animals, bacteria and fungi as innate immunity and this enzyme as therapeutic agents can be a promising host defense factors [82]. The antimicrobial peptides approach in combating drug-resistant bacteria. Gill et database (APD) currently contains 183 bacteriocins, al. engineered the first lysozyme protein specifically 291 plant AMPs, and 1648 animal host defense designed to exhibit enhanced stability. This compound peptides. APD contains peptides from various biological was active against Gram-negative (P. aeruginosa) sources (bacteria, plant, animal, and human), and and Gram-positive (Micrococcus luteus) bacteria and with various biological activities including antibacterial, was found to be more efficient than the natural human antifungal, antiviral (including anti-HIV), anticancer, lysozyme [90]. antiparasitic, insecticidal, spermicidal and chemotactic Monoclonal antibodies (mAbs) have also been activity. It was established in 2003 and is expanding [83; considered as potential agents in narrow-spectrum http://aps.unmc.edu/AP/main.php]. antibacterial therapy. The advantage of such therapy is AMPs play a crucial role in the human immune a high degree of specificity against bacterial targets that system. They usually destroy bacterial cells by interaction do not possess human homologs. One example is the with and destabilization of bacterial membranes. The C. difficile mAb combination, MK-3415A and MK-6072 primary advantage of AMPs as antimicrobial agents (Merck), currently undergoing phase 3 clinical trials [91, is their broad spectrum of activity. A large variety of www.clinicaltrials.gov]. Several monoclonal antibodies human proteins and peptides have antibacterial and that target different P. aeruginosa cell proteins (e.g. antifungal activity (e.g. defensins, cathelicidins and KB001-A, KaloBios Pharmaceuticals), are also in clinical histatins). Some of them also demonstrate antiviral and development [11, www. clinicaltrials.gov]. KB001-A anticancer properties. The mode of action of defensins shows anti-infective and anti-inflammatory properties and cathelicidins is based on electrostatic binding of the and is developed for the treatment of patients suffering cationic peptide to the outer surface of the pathogen, from cystic fibrosis and those chronically infected with followed by insertion of the peptide into the cytoplasmic P. aeruginosa [92]. Although promising, at present

951 New perspectives on antibacterial drug research

there are no FDA-approved mAbs for treating bacterial It is also essential to increase vaccine uptake (anti- infections, as their safety and action still needs to be pneumococcal, anti-meningococcal, anti-Haemophilus investigated. influenza, etc.), especially by those in high-risk groups. Attempts have also been made to combine antibiotics Vaccines and diagnostics play an important role in the with other agents, such as natural bioactive substances, rational use of antibiotics and in preventing infections. One to enhance their antibacterial activity. Examples include of the WHO recommendations encourages cooperation associating conventional antibiotics (like , between industry, government bodies and academic gentamicin, , ) with thyme oils, institutions in the search for new drugs and vaccines [99]. or β-lactams with epigallocatechin gallate [93,94]. Such combinations (antibiotic with natural extracts) may allow antibiotics to be used at a lower dose or 6. Conclusions reduced frequency of application, and thus decrease their toxicity and development of resistance. However, The Infectious Diseases Society of America, in response these applications need further investigation, as natural to the continued increase in antimicrobial resistance, bioactive compounds can occasionally lower antibiotic proposed the “10x20 Initiative”, in which it calls for the activity or interact with them. development of 10 new, safe and effective antimicrobials In addition to the development of novel antimicrobial by 2020 [100]. Antibiotic resistance is an international compounds, the World Health Organization (WHO) problem. MDR pathogens are responsible for health- has called for improved surveillance of antimicrobial care associated infections. The present outlook in the resistance (AMR), the rational use of antibiotics in antibacterial drug market is not satisfactory, despite many humans and animals, and better prevention and successes in the laboratory. Emergence of MDR bacteria control of infections [95]. Effective surveillance requires creates the necessity to seek novel antibiotics with new strengthening the laboratory capacity for AMR detection, modes of action, including antibacterial compounds enabling a prompt flow of information from laboratories with original chemical structures, as well as alternate to prescribers and national/subnational policy-making drug targets. Compounds with dual modes of action authorities, and ensuring that the information is are promising for antimicrobial therapy (e.g. inhibitors appropriately used [96]. Other important issues should of gyrase/topoisomerase IV). In this review we list many also be monitored, like certified quality of the drug, chemical moieties that are currently under investigation. regulating drug promotion and improving dispensing Clinical trials of the compounds mentioned are mostly and access to antibiotics [97]. directed to the therapy of SSSI, CAP, IAI, and UTI. In WHO emphasizes the need for infection prevention this work, we report on some alternatives to antibiotics, and control (IPC) in all health facilities, addressing the such as bacteriophages, antimicrobial peptides, essential components (infrastructure, organizational monoclonal antibodies and natural oils. Unfortunately, aspects, laboratory support, human resources, these approaches still do not have broad application in protocols and practices) and linking them to public health medicine. The success of the next wave of antibiotics services. WHO also proposed the roles, responsibilities will also require changes in in law regulations, clinical and activities of national authorities in implementing domains and reimbursement of medical expenses, for functioning IPC programs (e.g. IPC education in relation which considerable challenges lie ahead [11]. to AMR in medical and nursing studies). Some countries (Australia, Belgium, England, France, Malaysia) have successfully introduced national strategies to combat Acknowledgements AMR. For example, media campaigns to decrease antibiotic usage, admission screening and isolation, and This work was partially supported by the EU, Ministry of reporting of mandatory indicators in France caused a Regional Development, UDA-POIG.01.03.01-14-136/09 41% reduction of MRSA infections [98]. grant.

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