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 antibiotics is constantly increasing. Bacteria particularly dangerous for human life are methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium and fluoroquinolone-resistant Pseudomonas aeruginosa. 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 antibiotic 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, Streptococcus pneumoniae 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. “Antimicrobial resistance 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 cephalosporins (e.g. antibiotic, alteration of the target, drug efflux or reduced ceftobiprole and ceftaroline) and quinolones, which permeability of the cell wall [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. daptomycin (2003), aureus (methicillin-resistant), C. difficile, Acinetobacter telithromycin (2004), tigecycline (2005), retapamulin baumannii, Pseudomonas aeruginosa (fluoroquinolone- (2007), ceftobiprole medocaril (2008), ceftaroline resistant) and Enterobacteriaceae species [7]. The fosamil (2010), telavancin (2009), fidaxomicin (2011), abbreviation “ESCAPE” was proposed by Peterson in biapenem (2002), ertapenem (2002), doripenem (2005) 2009 to replace the previous “ESKAPE” which included and tebipenem 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 prulifloxacin (2002), pazufloxacin (2002), balofloxacin (offered by Rice in 2008, [8]). The change of abbreviation (2002), gemifloxacin mesylate (2004), garenoxacin (“ESKAPE”) was related to increasing importance and (2007), sitafloxacin (2008), besifloxacin (2009), threat of other bacterial species. Master et al. reported antofloxacin (2009), oxazolidinones (linezolid, 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 imipenem increased from 23.9% to 34.3% during the Ceftobiprole, a new cephalosporin, is active against period from 2007 to 2011. K. pneumoniae resistance to MRSA and penicillin-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 carbapenems, 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 ketolide protein synthesis 2001 Europe, 2004 FDA [38] tigecycline glycylcycline protein synthesis 2005 [34] retapamulin pleuromutilin protein synthesis 2007