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b-Lactams and b-Lactamase Inhibitors: An Overview

Karen Bush1 and Patricia A. Bradford2

1Molecular and Cellular Biochemistry, Indiana University, Bloomington, Indiana 47405 2AstraZeneca Pharmaceuticals, Waltham, Massachusetts 02451 Correspondence: [email protected]

b-Lactams are the most widely used class of . Since the discovery of benzylpeni- cillin in the 1920s, thousands of new derivatives and related b-lactam classes of , , , and have been discovered. Each new class of b-lactam has been developed either to increase the spectrum of activity to include additional bacterial species or to address specific resistance mechanisms that have arisen in the targeted bacterial population. Resistance to b-lactams is primarily because of bacterially produced b-lactamase that hydrolyze the b-lactam ring, thereby inactivating the drug. The newest effort to circumvent resistance is the development of novel broad-spectrum b-lactamase inhibitors that work against many problematic b-lac- tamases, including cephalosporinases and serine-based carbapenemases, which severely limit therapeutic options. This work provides a comprehensive overview of b-lactam anti- biotics that are currently in use, as well as a look ahead to several new compounds that are in the development pipeline.

hen Alexander Fleming was searching for a consortium of scientists from England and the Wan antistaphylococcal bacteriophage in United States were able to optimize the isolation his laboratory in the 1920s, he deliberately left and identification of to assist in plates out on the bench to capture airborne the treatment of Allied soldiers in World War II agents that might also serve to kill staphylococci (Macfarlane 1979). These activities set the stage

www.perspectivesinmedicine.org (Fleming 1929). His success was greater than he for the launch of the most successful class of must have hoped for. His initial publication on antibiotics in history. benzylpenicillin described a substance that was b-Lactam antibiotics are currently the most unstable in aqueous solution but that might used class of antibacterial agents in the in- serve as an antiseptic or as a selective agent for fectious disease armamentarium. As shown in isolation of Gram-negative that were Figure 1, b-lactams account for 65% of all present in mixed cultures of staphylococci and prescriptions for injectable antibiotics in the streptococci. As the potential utility of penicillin United States. Of the b-lactams, cephalosporins G as a parenteral therapeutic agent became comprise nearly half of the prescriptions (Table more obvious, Fleming, Abraham, Florey, and 1). The b-lactams are well tolerated, efficacious,

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Tetracyclines Trimethoprim/sulfa Macrolides/ketolides Fluoroquinolones Aminoglycosides Glycopeptides All other antibacterials β-Lactams

Figure 1. Proportion of prescriptions in the United States for injectable antibiotics by class for years 2004–2014. The percentage of standard units for each injectable antibiotic prescribed in the United States from 2004 to 2014 is shown as follows: b-lactams, 65.24%; glycopeptides, 9%; fluoroquinolones, 8%; macrolides/ketolides, 6%; aminoglycosides, 5%; polymyxins, 1%; trimethoprim/sulfamethoxazole, 0.5%; tetracyclines (excluding tigecy- cline), 0.4%; all other antibiotics (including , linezolid, and tigecycline), 4.21%. (Data from the IMS MDART Quarterly Database on file at AstraZeneca.)

and widely prescribed. Their major toxicity is by b-lactams is perceived to be a major advan- related to an allergic response in a small per- tage in the treatment of serious infections. centage of patients who react to related side When these agents were threatened by the rapid chain determinants; notably, these reactions emergence of b-lactamases, b-lactamase-stable are most common with and cepha- agents were developed, as well as potent b-lac- losporins with minimal reactivity caused by tamase inhibitors (BLIs). In this introductory monobactams (Saxon et al. 1984; Moss et al. description of the b-lactams, the most com- 1991). The bactericidal mechanism of killing monly available b-lactams and BLIs will be pre- sented, with a brief summary of their general

www.perspectivesinmedicine.org characteristics. Occasional agents have been in- Table 1. Usage of parenteral b-lactams by class from cluded for their historical or scientific impor- 2004–2104 in the United States tance. Note that resistance mechanisms will Percentage of be discussed in detail in other articles in this Class of b-lactam prescriptionsa collection. Narrow spectrum penicillins 3.12 Broad spectrum penicillinsb 36.54 MECHANISM OF ACTION Cephalosporins 47.49 Monobactams 1.66 b-Lactam antibiotics are bactericidal agents Carbapenems 11.20 that interrupt bacterial cell-wall formation as aThe percentage for each injectable antibiotic class a result of covalent binding to essential penicil- prescribed in the United States from 2004 to 2014. (Data lin-binding proteins (PBPs), enzymes that are from the IMS MDART Quarterly Database on file at involved in the terminal steps of AstraZeneca.) bBroad-spectrum penicillins include the b-lactam/ cross-linking in both Gram-negative and Gram- b-lactam-inhibitor combinations -, positive bacteria. Every bacterial species has its -clavulanate, and -. own distinctive set of PBPs that can range from

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b-Lactams and b-Lactamase Inhibitors

three to eight enzymes per species (Georgopa- PENICILLINS padakou and Liu 1980). The inhibition of bac- terial peptidoglycan transpeptidation by penicil- Penicillin G (benzylpenicillin) was the first b- lin was described mechanistically in a classical lactam to be used clinically, most frequently to paper by Tipper and Strominger (1965), who treat streptococcal infections for which it had noted a structural similarity of penicillin G to high potency (Rammelkamp and Keefer 1943; the terminal D-Ala-D-Ala dipeptide of the na- Hirsh and Dowling 1946). Another naturally scent peptidoglycan in the dividing bacterial occurring penicillin, penicillin V (phenoxy- cell. This mechanism is now known to involve methylpenicillin), in an oral formulation is still binding of penicillin, or another b-lactam, to an used therapeutically and prophylactically for active site serine found in all functional PBPs mild to moderate infections caused by suscep- (Georgopapadakou et al. 1977). The resulting tible Streptococcus spp., including use in pedi- inactive acyl may then slowly hydrolyze atric patients (Pottegard et al. 2015). However, the antibiotic to form a microbiologically inac- the selection of penicillin-resistant penicillin- tive entity (Fre`re and Joris 1985). In addition to ase-producing staphylococci in patients treated these functionalities, recent work has shown with penicillin G led to decreased use of this the binding of selected b-lactams, such as cef- agent, and prompted the search for more pen- taroline, to an allosteric site in PBP2a from icillins with greater stability to the staphylococ- , resulting in an increased cal b-lactamases (Kirby 1944, 1945; Medeiros sensitization of the organism to the antibiotic 1984). A list of historically important and clin- (Otero et al. 2013; Gonzales et al. 2015). ically useful penicillins is provided in Table 2. PBPs may be divided into classes according Among the penicillinase-stable penicillins of to molecular mass (Goffin and Ghuysen 1998; clinical significance are , , Massova and Mobashery 1998), with low-mo- , and , with the latter suggest- lecular-mass PBPs serving mainly as mono- ed as the b-lactam of choice for skin infections, functional D-Ala-D-Ala carboxypeptidases. catheter infections, and bacteremia caused by High-molecular-mass PBPs have been divided methicillin-susceptible S. aureus (Bamberger into two subclasses, one of which (class A) in- and Boyd 2005). All were used primarily for cludes bifunctional enzymes with both a trans- staphylococcal infections until the emergence peptidase and a transglycosylase domain, and of methicillin-resistant S. aureus (MRSA) in the second of which (class B) encompasses D- 1979–1980 (Hemmer et al. 1979; Saroglou et Ala-D-Ala-dependent transpeptidases. At least al. 1980). one PBP is deemed to be essential in each spe- Penicillins with improved activity against www.perspectivesinmedicine.org cies, with a unique specificity for b-lactam Gram-negative pathogens included the orally binding that varies among each species and bioavailable ampicillin and , both each b-lactam class (Curtis et al. 1979; Georgo- of which were introduced in the 1970s. These papadakou and Liu 1980). In Gram-negative agents were initially used for the treatment of bacteria, essential PBPs include the high-molec- infections caused by Enterobacteriaceae and did ular-weight PBPs 1a and 1b that are involved not effectively inhibit the growth of Pseudomo- in cell lysis, PBP2, the inhibition of which re- nas aeruginosa, which became more of a con- sults in a cessation of cell division and the for- cern during the late 1970s. was mation of spherical cells, and PBP3 for which the first antipseudomonal penicillin to be in- inhibition arrests cell division, resulting in fila- troduced, but lacked stability to b-lactamase mentation. Cell death may occur as a result of hydrolysis and was less potent than piperacillin inhibiting one or more of these PBPs (Spratt or ticarcillin, later antipseudomonal penicil- 1977, 1983). The roles of PBPs in Gram-positive lins. These latter drugs were considered to be bacteria and Mycobacterium tuberculosis are potent broad-spectrum penicillins that includ- discussed in detail in Fisher and Mobashery ed penicillin-susceptible staphylococci, enteric (2016). bacteria, anaerobes, and P. aeruginosa in their

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O R1 R2 C HN S CH3 dacdOln ril.Ct hsatceas article this Cite Article. Online Advanced N CH3

O CO2H Route of b,c Name R1 R2 administration Approval date Status Benzylpenicillin (penicillin G) —H IM or IV 1946 Approved worldwide H2C onOctober4,2021-PublishedbyColdSpringHarborLaboratoryPress —H Oral 1968 Approved worldwide O CH2 (penicillin V)

Methicillin —H OCH3 IV 1960 No longer available; of historical interest odSrn abPrpc Med Perspect Harb Spring Cold

OCH3 Oxacillin —H Oral, IV 1962 Widely available, but not in the United Kingdom

N O CH3 Cloxacillin —H Cl Oral, IV 1974 Widely available, but not in the United o:10.1101 doi: Kingdom

/ N cshperspect.a025247 O CH3

Ampicillin —H NH2 Oral, IV 1963 Widely available

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Table 2. Continued http://perspectivesinmedicine.cshlp.org/ dacdOln ril.Ct hsatceas article this Cite Article. Online Advanced Route of b,c Name R1 R2 administration Approval date Status Nafcillin —H IV 1970 Limited availability

O

Amoxicillin —H NH2 Oral, IV 1972 Widely available

HO

Carbenicillin —H H Oral 1972 Discontinued onOctober4,2021-PublishedbyColdSpringHarborLaboratoryPress odSrn abPrpc Med Perspect Harb Spring Cold C O HO Ticarcillin —H H IV 1976 Limited availability C O S HO Piperacillin —H IV 1981 Widely available, primarily in O combination with tazobactam o:10.1101 doi: N N N H and b-Lactams O O / cshperspect.a025247 —OCH H IV 1985 in Europe Limited availability (Europe) 3 C (Harvengt 1985) O

S HO Inhibitors b-Lactamase IV 1978 Limited availability N N S CH3

N CH3 O CO2H IM, Intramuscular; IV, intravenous. a 5 FDA approval unless otherwise noted. bDates were updated from Medeiros (1997) (www.accessdata.fda.gov/scripts/cder/drugsatfda; www.drugs.com). Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press

K. Bush and P.A. Bradford

spectrum of activity. They were used extensively CEPHALOSPORINS to treat serious nosocomial infections, especial- ly when combined with a b-lactamase inhibitor During the 1950s, the discovery of the naturally (see below). occurring penicillinase-stable C Two parenteral penicillins with unusual opened a new pathway to the development of chemical structures, mecillinam and temocillin hundreds of novel cephalosporins (Newton and (Table 2), were introduced to treat infections Abraham 1956; Abraham 1987) to treat infec- caused by enteric bacteria before the global tions caused by the major penicillinase-pro- emergence of extended-spectrum b-lactamases ducing pathogen of medical interest at that (ESBLs) in the late 1980s. Mecillinam (also time, S. aureus. Dozens of cephalosporins were known as amdinocillin), with a 6-b-amidino introduced into clinical practice (Abraham side chain, is a narrow-spectrum b-lactam that 1987), either as parenteral or oral agents. The binds exclusively to PBP2 in enteric bacteria molecules exhibited antibacterial activity with (Curtis et al. 1979). Because of this specificity, MICs often 4 mg/ml against not only staph- it shows synergy in vitro in combination with ylococci, but also Streptococcus pneumoniae and other b-lactams that bind to PBPs 1a/1b and/ non-b-lactamase-producing enteric bacteria. or PBP3 in Gram-negative bacteria (Hanberger The parenteral agents were generally eightfold et al. 1991), thus decreasing the possibility that more potent than the oral agents that were used a point mutation in a single PBP would lead in some cases to replace oral penicillins in pen- to resistance (Hickman et al. 2014). Temocillin, icillin-allergic patients. The early cephalospo- the 6-a-methoxypenicillin analog of ticarcillin, rins, for example, those in the cephalosporin had greater stability than ticarcillin to hydrolysis I subclass (Bryskier et al. 1994) introduced by serine b-lactamases, but lost antibacterial before 1980, were labile to hydrolysis by many activity against Gram-positive bacteria, anaero- b-lactamases that emerged following their in- bic Gram-negative pathogens, and some enteric troduction into clinical practice, so that only a bacteria that included the important pathogens few of the early molecules remain in use (see Enterobacter spp. and Serratia marcescens (Mar- Table 3), primarily to treat mild to moderate tinez-Beltran et al. 1985). Mecillinam and te- skin infections caused by methicillin-suscepti- mocillin are currently enjoying a resurgence in ble S. aureus (MSSA) (Giordano et al. 2006). interest owing to their stability to many ESBLs with high biliary concentrations is (Livermore et al. 2006; Rodriguez-Villalobos still used for surgical prophylaxis and for treat- et al. 2006), often resulting in greater than ment of abdominal infections (Sudo et al. 2014) 90% susceptibility when tested against many and is effective as empiric therapy in 80% of www.perspectivesinmedicine.org contemporary ESBL-producing Enterobacter- Japanese children with their first upper urinary iaceae (Giske 2015; Zykov et al. 2016). tract infection (Abe et al. 2016). Because increasing numbers of b-lactamas- When the TEM-1 penicillinase began to ap- es have compromised the use of penicillins as pear on transmissible plasmids in Neisseria gon- single agents (Bush 2013), there is currently orrhoeae (Ashford et al. 1976) and Haemophilus limited therapeutic use of the penicillins as influenzae (Gunn et al. 1974; Khan et al. 1974), monotherapy. Ampicillin, amoxicillin, pipera- it was quickly recognized that the penicillins cillin, and ticarcillin have continued to be use- and cephalosporins in medical use were becom- ful, primarily as a result of their combination ing ineffective, not only in treating those TEM- with an appropriate b-lactamase inhibitor (see 1-producing organisms, but also for the enteric below). However, even ampicillin, amoxicillin, bacteria and P. aeruginosa that could all acquire penicillin G, and penicillin V are still active this enzyme. Another surge of synthetic activ- as monotherapy against Group A streptococci, ity in the provided and Treponema pallidum, two of the few bacte- both oral and parenteral cephalosporins with rial species that do not produce b-lactamases stability to this common enzyme. These agents (Schaar et al. 2014). tended to have decreased potency against the

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Table 3. Cephalosporins of current clinical utility or of historical interest

HN R2 R3 S

O N O R1

O OH

Route of a b,c Name Subclass R1 R2 R3 administration Approval date Status

Cephalexin Cephalosporin I H –H –CH Oral 1971 Limited availability onOctober4,2021-PublishedbyColdSpringHarborLaboratoryPress C 3

NH2

Cefaclor Cephalosporin I –Cl –H NH2 Oral 1979 Widely available

Cefixime Cephalosporin V –H OH Oral 1989 Widely available

N O N H2N S

Cefpodoxime Cephalosporin IV O –H N Oral 1992 Widely available CH3 N H2N S O CH3 Ceftibutin Cephalosporin III –H –H O Oral 1995 Widely available N H2N OH S Continued Downloaded from

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Table 3. Continued Route of a b,c Name Subclass R1 R2 R3 administration Approval date Status Cephalosporin V –H HO Oral 1997 Widely available N H2N N S Cefazolin Cephalosporin I S S –H N IV 1973 Widely available N N N N N onOctober4,2021-PublishedbyColdSpringHarborLaboratoryPress d Cephalosporin II O NH2 –H H C O Oral, IV 1983 Widely available 3 N O O

Cefotaxime Cephalosporin III O CH3 –H CH3 IV 1981 Widely available O O N N H2N S Cephalosporin III –H OH IV 1982 Widely available S N N N N O N N N H O O

Ceftriaxone Cephalosporin III S N O –H CH3 IV 1984 Widely available O N N N O H N H2N S Continued Downloaded from

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Table 3. Continued http://perspectivesinmedicine.cshlp.org/ Route of a b,c Name Subclass R1 R2 R3 administration Approval date Status Cephalosporin III –H OH IV 1985 Widely available + O N H3C C CH O 3 N N H2N S

Cefepime Cephalosporin IV –H CH3 IV 1996 Widely available N+ O N onOctober4,2021-PublishedbyColdSpringHarborLaboratoryPress N H2N S Me OCH CH Ceftaroline Anti-MRSA + –H 2 3 IV 2010 Widely available (fosamil) cephalosporin N N H N N H2O3P S N N

S S

Ceftobiprole Anti-MRSA NH –H OH IV 2013 (Europe) Limited availability cephalosporin N N H2N N O S N

Ceftolozane Antipseudomonal NH2 –H CH3 IV 2014 Limited availability H C CO H cephalosporin– HN 3 2 cephalosporin VI HN N O O H2N N NH N 2 S N + N Me

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Table 3. Continued Route of a b,c Name Subclass R1 R2 R3 administration Approval date Status S-649266 O Cl –H OH IV Not approved Phase 2 H C O cephalosporin– N+ OH 3 cephalosporin V N C CH H O 3 OH N N H2N onOctober4,2021-PublishedbyColdSpringHarborLaboratoryPress S

Cefoxitin O NH2 –OCH3 IV 1978 Widely available S O Moxalactam HO IV 1982e Limited availability

O OCH3 HO O HN O N S N O N N N O OH IM, Intramuscular; IV, intravenous. aSubclasses assigned according to CLSI (2016), Bryskier et al. (1994), or Bryskier and Belfiglio (1999). bFDA approved unless otherwise noted. cDates were updated from Medeiros (1997) (www.accessdata.fda.gov/scripts/cder/drugsatfda; www.drugs.com; www.price-rx.com/lists/lantibiotics.shtml). dOral when dosed as . eAnonymous (1982). Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press

b-Lactams and b-Lactamase Inhibitors

staphylococci, but gained antibacterial activity ished activity against staphylococci and entero- against Gram-negative pathogens. Cefuroxime, cocci compared to earlier cephalosporins, but dosed parenterally or orally as the axetil ester, have more potent activity against Gram-nega- was the only member of the cephalosporin II tive organisms. tends to have lower class (Bryskier et al. 1994) with both oral and MICs against enteric bacteria than the other systemic dosage forms, but its stability to b-lac- expanded-spectrum cephalosporins, attributed tamase hydrolysis was diminished compared to to greater penetration through the OmpF outer- later oral cephalosporins (Jacoby and Carreras membrane porin protein (Nikaido et al. 1990; 1990). As seen with cefuroxime, acceptable oral Bellido et al. 1991). and of required esterifi- are often used to treat susceptible streptococcal cation through addition of a proxetil group to infections; all can be used to treat serious infec- attain sufficient absorption for efficacy (Brys- tions caused by enteric bacteria if the organisms kier and Belfiglio 1999). Of the oral agents test susceptible. Notably, ceftazidime and cefe- approved after 1983 in Table 3, cefdinir was pime have maintained their observed activity generally more stable to hydrolysis, not only against P. aeruginosa, with recent susceptibility to the original TEM enzyme, but also to the rates exceeding 80% (Sader et al. 2015). A lia- AmpC cephalosporinases that are produced at bility of the expanded-spectrum cephalospo- a basal level in many enteric bacteria and rins, however, began to emerge only a few years P. aeruginosa (Payne and Amyes 1993; Labia after the introduction of cefotaxime, when the and Morand 1994). ESBLs were identified with the ability to hydro- Among the parenteral agents introduced in lyze all of the b-lactams, with the exception of the 1980s were the cephamycin , and the carbapenems. These enzymes, in addition to cephalosporins in the cephalosporin III and both serine and metallo-carbapenemases, have cephalosporin IV subclasses (Bryskier et al. severely compromised the activity of almost all 1994), which continue to serve as important penicillins and cephalosporins, necessitating antibiotics for the treatment of serious infec- the development of combination therapy with tions caused by Gram-negative pathogens. The other b-lactams, b-lactamase inhibitors, or an- novel oxacephem moxalactam, or , tibiotics from other classes. which had similar antimicrobial activity to the Ceftolozane, recently approved in combi- cephalosporin III/IV subclasses, has exquisite nation with tazobactam for the treatment of stability to hydrolysis by b-lactamases (Sato complicated urinary tract infections and com- et al. 2015), but was not a highly successful an- plicated intraabdominal infections, shows po- tibiotic owing, in part, to a relatively high fre- tent antipseudomonal activity, and includes www.perspectivesinmedicine.org quency of bleeding in patients treated with this activity against enteric bacteria that produce drug (Brown et al. 1986). The cephamycin ce- some ESBLs (Zhanel et al. 2014), particularly foxitin is notable for its characteristic 7-me- CTX-M-producing isolates (Estabrook et al. thoxy side chain that confers stability to the 2014). Another recent addition to the cephalo- TEM-type b-lactamases, including ESBLs. It sporin family is the siderophore-substituted has useful antibacterial activity against MSSA cephalosporin S-649266 with a catechol in the and enteric bacteria that do not produce high 3-position, thus allowing the molecule to enter levels of AmpC cephalosporinases (Jacoby and the cells via an iron transport mechanism (Ko- Han 1996). Cefotaxime, cefoperazone, ceftriax- hira et al. 2015). In addition to increased pen- one, and ceftazidime, designated as subclass etrability, the cephalosporin is stable to hydro- cephalosporin III, and cefepime in the cepha- lysis by many carbapenemases, resulting in losporin IV subclass, are also known as expand- activity against many b-lactam-resistant enteric ed-spectrum cephalosporins with increased bacteria (Kohira et al. 2015). hydrolytic stability to the common penicillinas- In the mid-1990s, reports began to emerge es, SHV-1 and TEM-1 b-lactamase (Martinez- describing cephalosporins with MICs ,4 mg/ Martinez et al. 1996). These agents have dimin- ml against MRSA (Hanaki et al. 1995) as a result

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of targeted binding to PBP2a. PBP2a is an ac- general, bind strongly to PBP2 in Gram-nega- quired low-affinity PBP responsible for the tive bacteria, but may also bind to PBP1a, 1b, observed lack of antibacterial activity of most and 3, thus providing supplemental killing b-lactams in MRSA isolates. (Ha- mechanisms that may serve to lessen the emer- naki et al. 1995; Hebeisen et al. 2001) and cef- gence of resistance (Sumita and Fukasawa 1995; taroline (Moisan et al. 2010), two cephalospo- Yang et al. 1995). Carbapenems are notable for rins with IC50 values ,1 mg/ml for binding to their stability to most b-lactamases (Bonfiglio the staphylococcal PBP2a, have been developed et al. 2002), with the exception of the emerging for clinical use (Table 3). Ceftaroline is approx- carbapenemases found primarily in Gram-neg- imately twofold to fourfold more potent than ative bacteria (Bush 2013). Because of the labil- ceftobiprole in inhibiting staphylococcal and ity of to hydrolysis by the human streptococcal growth (Karlowsky et al. 2011), renal dehydropeptidase (DHP) causing inacti- but ceftobiprole is up to fourfold more potent vation of the drug (Kropp et al. 1982), it is dosed against Enterococcus faecalis (Karlowsky et al. in combination with , a DHP inhibitor 2011). Ceftobiprole generally has at least four- that also acts as a nephroprotectant (Kahan et fold to eightfold lower MICs than ceftaroline al. 1983). against enteric bacteria, P. aeruginosa, and Aci- Based on the potent broad-spectrum activ- netobacter spp. (Pillar et al. 2008; Karlowsky ity of the early carbapenems, other related et al. 2011). Neither cephalosporin is stable to agents, including , , and hydrolysis by ESBLs or carbapenemases (Pillar , have been developed for global use, et al. 2008; Castanheira et al. 2012), although with generally the same group of organisms in- the combination of ceftaroline with the b-lac- cluded in their activity spectrum (Baughman tamase inhibitor overcomes many of 2009). All these carbapenems are more stable these issues (Mushtaq et al. 2010; Flamm et al. chemically than imipenem, thus allowing for a 2014) (see below). Both drugs are highly insol- longer shelf life for the formulated drug and the uble and have been derivatized as prodrugs for potential for prolonged infusion times (Cie- therapeutic use, as (Talbot lecka-Piontek et al. 2008; Prescott et al. 2011). et al. 2007) and ceftobiprole medocaril (He- Like imipenem, they are stable to most b-lacta- beisen et al. 2001), respectively. mases, other than the carbapenemases (Bush 2013). Following the introduction of imipen- em, later carbapenems contained a 1b-methyl CARBAPENEMS group that conferred stability to the human was identified in the mid-1970s DHP, thus negating the necessity for coadmin- www.perspectivesinmedicine.org as a potent broad-spectrum antibiotic with istration of an inhibitor such as cilastatin (Zha- the typical four-membered b-lactam structure nel et al. 2007). In terms of antibacterial activity, fused to a novel five-membered ring in which meropenem is generally twofold to fourfold carbon rather than was present at the more potent that imipenem against enteric bac- 1-position (Kahan et al. 1979). Because of its teria (Jorgensen et al. 1991), is similar in poten- chemical instability, this was never cy against P. aeruginosa, but may have twofold developed as a therapeutic agent, but was stabi- to eightfold less antibacterial activity against lized by adding the N-formimidoyl group to Gram-positive bacteria (Neu et al. 1989). In the 2-position, resulting in imipenem (Table addition, meropenem and doripenem retain 4). Imipenem has been widely used for infec- greater activity against isolates of P. aeruginosa tions caused by Gram-positive, Gram-negative, lacking the outer membrane porin protein nonfermentative, and anaerobic bacteria based OprD than imipenem (Riera et al. 2011). Mer- on its sustained high activity against these or- openem is the only carbapenem approved for ganisms, particularly among non-carbapene- use in meningitis because of its excellent pene- mase-producing enteric bacteria (Bradley et al. tration into the meninges (Dagan et al. 1994). 1999; Kiratisin et al. 2012). Carbapenems, in Doripenem, a carbapenem with somewhat

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b-Lactams and b-Lactamase Inhibitors

Table 4. Carbapenems of current clinical utility OH R1

R N 2 O OH O

a,b Name R1 R2 Approval date Status Imipenem H H NH 1985 Widely available N H S O Meropenem CH3 H 1996 Widely available N N

S

Ertapenem CH3 CO2H 2001 Widely available

O N H NH S Doripenem CH H O O 2007 Widely available 3 N S N NH H 2 S CH N 2001 (Japan) Available in Japan 3 N N+

S c CH3 S 2009 (Japan) Available in Japan N N

S www.perspectivesinmedicine.org aFDA approved unless otherwise noted. bDates were updated from Medeiros (1997) (www.accessdata.fda.gov/scripts/cder/drugsatfda; www.drugs.com; adisin sight.springer.com/drugs/800010812). cFormulated as the pivoxil ester.

higher chemical stability than imipenem or dosed most commonly two or three times a meropenem (Prescott et al. 2011), follows the day. Although its antibacterial spectrum is sim- antibacterial profile of meropenem, but is ilar to the other carbapenems against Entero- slightly more potent against Gram-negative or- bacteriaceae, ertapenem differs from imipenem, ganisms (Nordmann et al. 2011). Ertapenem, meropenem, and doripenem in that it has no recognized for its long elimination half-life in useful activity against P.aeruginosa (Kohler et al. humans because of its high protein binding 1999). Two carbapenems approved for use only (95%) (Majumdar et al. 2002), may be effective- in Japan include biapenem, with an antimicro- ly administered once daily (Kattan et al. 2008) bial spectrum similar to meropenem and dor- in contrast to the other carbapenems that are ipenem (Neu et al. 1992; Papp-Wallace et al.

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K. Bush and P.A. Bradford

2011), and tebipenem, which lacks appreciable bic enteric bacteria and P. aeruginosa, with antipseudomonal activity (Fujimoto et al. MICs against S. aureus, S. pneumoniae, and 2013) (Table 4). Tebipenem is notable for its E. faecalis 50 mg/ml (Sykes et al. 1982). It dosing as the pivoxil ester, rendering it orally binds tightly to PBP3 in Gram-negative rods, bioavailable for use in pediatric respiratory in- with weaker binding to PBP1a, leading to fila- fections (Kato et al. 2010). Like the other carba- mentation followed by cell lysis (Sykes et al. , they are stable to hydrolysis by most 1982). At the time that it was introduced into serine b-lactamases, but can be hydrolyzed by clinical practice, was stable to hydro- both serine and metallo-carbapenemases. Bia- lysis by all of the common b-lactamases (Sykes has been reported to have better hydro- et al. 1982); the emergence of ESBLs and the lytic stability to metallo-b-lactamases (MBLs) serine carbapenemases has since rendered it compared to imipenem or meropenem (Neu less effective against multidrug-resistant b- et al. 1992; Inoue et al. 1995; Yang et al. 1995) lactamase-producing organisms (Wang et al. with at least fourfold lower MICs than imipe- 2014). However, the nucleus is nem when tested against organisms producing not a good substrate for hydrolysis by MBLs, IMP, VIM, or NDM MBLs (Livermore and thus leading to a unique opportunity for this Mushtaq 2013). monobactam to be used in combination thera- py with a serine b-lactamase inhibitor to treat infections caused by multi-b-lactamase-pro- MONOCYCLIC b-LACTAMS ducing bacteria (see below) (Wang et al. 2014). Aztreonam, a monocyclic b-lactam with an BAL30072 is a novel monosulfactam with N1-sulfonic acid substituent, originated as a de- an N1-O-sulfate group, an activity-enhancing rivative from a novel antibiotic isolated from 3-dihydropyridone siderophore substituent, the New Jersey Pine Barrens (Cimarusti and and a 4-gem-dimethyl substitution on the aze- Sykes 1983) (Table 5), and is the only mono- tidinone ring (Page et al. 2010) (Table 5). Its bactam to gain regulatory approval for thera- spectrum of activity is similar to aztreonam, peutic use. It has targeted activity against aero- but supplemented with activity against addi-

Table 5. Monocyclic b-lactams R2 X N O R1 www.perspectivesinmedicine.org

Name Subclass R1 R2 Approval date Status a Aztreonam Monobactam —SO3H O 1986 Widely available X ¼ a-methyl N C HNC N H2N S O C H C CH3 3 - CO2

BAL30072 Monosulfactam —OSO3H O Not approved Phase 1 X ¼ gem-dimethyl OH

N O N HO H2N N H N S O aU.S. approval date provided in Medeiros (1997).

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b-Lactams and b-Lactamase Inhibitors

tional nonfermentative bacteria. As a result of bination for nosocomial infections that include the increased penetration of BAL30072 via iron P. aeruginosa as a causative pathogen (Neu uptake mechanisms, it is more potent against 1990), and with amoxicillin as an orally bio- some Gram-negative bacteria than other b-lac- available formulation for therapeutic use espe- tams, with activity against Acinetobacter spp. cially in pediatric populations (Klein 2003). It is and Burkholderia spp. eightfold to .256-fold also used in phenotypic testing to determine the better than imipenem (Page et al. 2010). It is presence of ESBLs in and Kleb- susceptible to hydrolysis by ESBLs and many siella pneumoniae (Steward et al. 2001). carbapenemases, and has shown synergistic Following the discovery of , activity in combination with b-lactamase in- medicinal chemists synthesized a number of hibitors (Mushtaq et al. 2013) or meropenem penicillanic acid sulfones (Table 6) with b-lac- (Hofer et al. 2013; Hornsey et al. 2013). Like tamase inhibitory activity (English et al. 1978; aztreonam, it is stable to hydrolysis by MBLs; Fisher et al. 1981; Aronoff et al. 1984). Of these, additionally, it was hydrolyzed 3000-fold less sulbactam (English et al. 1978) and tazobactam efficiently by the KPC-2 serine carbapenemase (Aronoff et al. 1984) were successfully commer- compared to aztreonam (Page et al. 2010). cialized. Both had a similar spectrum of activity as clavulanic acid. Against class A b-lactamases, sulbactam had less inhibitory activity than clav- b-LACTAMASE INHIBITORS ulanic acid or tazobactam based on IC50 values, Attempts to identify inhibitors of common but both sulfones were better inhibitors of class b-lactamases began in the mid-1970s, triggered C cephalosporinase b-lactamases (Bush et al. by the appearance of the transferable TEM-1 1993). Each followed the same general inhibito- penicillinase in Neisseria gonorrhoeae (Ashford ry/inactivation-mechanism as for clavulanic et al. 1976) and Haemophilus influenzae (Gunn acid (Easton and Knowles 1984; Bush et al. et al. 1974; Khan et al. 1974). As the result of 1993). The number of hydrolytic events before natural product screening, clavulanic acid with inactivation was at least 25-fold higher for sul- a novel structure (Table6) was identified bactam than for clavulanic acid or tazobactam as a broad spectrum inhibitor of the staphylo- for the TEM-2 b-lactamase (Bush et al. 1993; coccal penicillinases and most of the recognized Easton and Knowles 1984). In contrast to clav- plasmid-encoded penicillinases found in enter- ulanic acid, the sulfone inhibitors do not func- ic bacteria (Reading and Cole 1977; Cole 1982), tion as inducers of chromosomally mediated including the highly prevalent TEM and SHV AmpC b-lactamase (Weber and Sanders 1990). enzymes (Simpson et al. 1980). The TEM b- Sulbactam has been combined with ampi- www.perspectivesinmedicine.org lactamase was shown to be inactivated by this cillin for general global use (Neu 1990) and with suicide inhibitor that initially acylates the active cefoperazone to provide additional synergistic site serine with transient inhibition that in- activity against nonfermentative and anaerobic cludes hydrolysis of the inhibitor before com- bacteria, primarily in Japan (Eliopoulos et al. plete enzyme inactivation (Charnas et al. 1978; 1989). Tazobactam has been combined with Charnas and Knowles 1981). The spectrum of piperacillin and, more recently, with cefopera- the inhibitor is now recognized to include most zone and ceftolozane for nosocomial infections, class A b-lactamases, including ESBLs (Steward including those caused by P. aeruginosa (Lister et al. 2001) and, to a lesser extent, serine carba- 2000). In general, none of the inhibitors has penemases (Nordmann and Poirel 2002; Yigit useful antibacterial activity as monotherapy, al- et al. 2003). Clavulanic acid acts synergistically though there are several notable exceptions. with penicillins and cephalosporins against b- Clavulanic acid alone has been reported to lactamase-producing enteric bacteria to inhibit have an MIC as low as 1 mg/ml against N. gon- sensitive b-lactamases, thus allowing the com- orrhoeae (Wise et al. 1978); sulbactam has mod- panion b-lactam to kill the bacteria. It has been est activity against wild-type Acinetobacter spp. combined with ticarcillin as a parenteral com- and Burkholderia cepacia, with MIC90 values

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K. Bush and P.A. Bradford

Table 6. b-lactamase inhibitors of current interest Partner b- Approval Name Structure Subclass lactam datea Status Clavulanic O OH Clavam Amoxicillin 1984 Widely b acid N available O O OH Sulbactamc O O Penicillanic Ampicillin 1986 Widely S acid available N sulfone O O OH Tazobactam O O Penicillanic Piperacillin 1993 Widely S N N N acid Ceftolozane 2014 available N sulfone Available in O the United O OH States and Europe Avibactamd O DBOe Ceftazidimed 2015 Widely available H2N N N - O OSO3 O DBO Imipenem Not Phase 3 in the HN approved United States + H2N N N - O OSO3 RG6080 O DBO Not selected Not Phase 1 O approved HN H2N N N O OSO -

www.perspectivesinmedicine.org 3 RPX7009 H Boronic acid Meropenem Not Phase 3 in the N S O approved United States O B HO O OH aDates provided in Medeiros (1997) or www.accessdata.fda.gov/scripts/cder/drugsatfda. bAlso initially combined with ticarcilllin to provide parenteral activity against . cAlso combined with cefoperazone outside the United States. dAlso in development with ceftaroline or aztreonam. eDiazabicyclooctane.

8 and 10 mg/ml, respectively (Jacoby and Sut- modest activity against serine carbapenemases ton 1989; Fass et al. 1990), but does not retain does not translate into clinical susceptibility activity against isolates with multiple resistance (Yigit et al. 2003; Woodford et al. 2004) owing, mechanisms (Dong et al. 2014). None of these at least in part, to the presence of multiple b- inhibitors is effective in inhibiting the hydro- lactamases in the producing organisms (Mo- lytic activity of MBLs (Bush 2015), and their land et al. 2007). Even the potent inhibitory

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activity against individual ESBLs that is ob- (Hecker et al. 2015), it is being developed in served with clavulanic acid and tazobactam is combination with meropenem to target patho- not sufficient to protect their accompanying gens producing serine carbapenemases (La- penicillins in the presence of multiple b-lacta- puebla et al. 2015). mases (Jones-Dias et al. 2014). Following a hiatus of approximately two decades, a unique class of non-b-lactam b-lac- b-LACTAM RESISTANCE: CONCLUDING tamase inhibitors emerged, based on a novel REMARKS bridged diazabicyclooctane (DBO) structure Resistance to the b-lactams continues to in- (Table 6) (Coleman 2011). The first of these crease, especially in Gram-negative organisms inhibitors, avibactam, has a broader spectrum (Vasoo et al. 2015), because of the widespread of activity than clavulanic acid and the sulfone therapeutic dependence on these efficacious inhibitors. Not only are class A penicillinases, and safe antibiotics (see Fig. 1). Major resistance ESBLs, and serine carbapenemases potently in- mechanisms will be expanded on in other hibited, but class C cephalosporinases and some articles in this collection. PBP acquisition or class D oxacillinases are also effectively inhibited mutation is the major b-lactam resistance (Ehmann et al. 2012, 2013). Unlike the previous mechanism in Gram-positive bacteria (see Fish- inactivators described above, avibactam is a er and Mobashery 2016). The most prevalent tight-binding, covalent, reversible inhibitor for and most damaging resistance mechanisms most enzymes, with the KPC-2 enzyme, a nota- among Gram-negative pathogens are represent- ble exception for which slow avibactam hydro- ed by the b-lactamases (Babic et al. 2006; Liv- lysis was observed (Ehmann et al. 2012). In ermore 2012), both chromosomally encoded addition, avibactam does not induce AmpC b- enzymes that may be produced at high levels lactamases at clinically relevant concentrations and transferable enzymes that travel on mobile (Coleman 2011). Avibactam has been approved elements among species (Bush 2013). When for therapeutic use in combination with cefta- these targeted mechanisms are combined with zidime, and is under development for ceftaro- decreased uptake or increased efflux of the b- line–avibactam or aztreonam–avibactam com- lactam, high-level resistance becomes a major binations (Flamm et al. 2014; Biedenbach et al. clinical problem (see Bonomo 2016). Perhaps 2015; Li et al. 2015). Other DBOs under devel- the most encouraging prospect in counteracting opment include RG6080 and relebactam (MK resistance is the emergence of new classes of b- 7655), in combination with imipenem. The lactamase inhibitors that will provide protec- spectrum of relebactam shows a similar spec- tion for some of the most valuable antibiotics www.perspectivesinmedicine.org trum of activity to avibactam; however, it pro- in clinical practice, at least for the present time. vides less potentiation against important class D b-lactamases such as OXA-48 (Livermore et al. 2013). RG6080 (formerly OP0565) is a DBO REFERENCES that has an inhibitory spectrum similar to the à other DBOs but has the additional benefit of Reference is also in this collection. exhibiting some intrinsic antibacterial activity Abe Y,Wakabayashi H, Ogawa Y,Machida A, Endo M, Tamai against enteric bacteria (Livermore et al. 2015). T,Sakurai S, Hibino S, Mikawa T,Watanabe Y,et al. 2016. The boronic acid inhibitor RPX7009 (Table Validation of cefazolin as initial antibiotic for first upper in children. Global Ped Health 3: 6) represents another novel class of synthetic 1–7. non-b-lactam b-lactamase inhibitors (Hecker Abraham EP. 1987. Cephalosporins 1945–1986. Drugs 34: et al. 2015), although boronic acids have been 1–14. known for many years to be effective inhibitors Anonymous. 1982. FDA approves new antibiotic for surgical of serine b-lactamases (Kiener and Waley 1978). infections, meningitis. Hospitals 56: 55–57. Aronoff SC, Jacobs MR, Johenning S, Yamabe S. 1984. Despite the inhibitory activity of RPX7009 Comparative activities of the b-lactamase inhibitors against many groups of serine b-lactamases YTR 830, sodium clavulanate, and sulbactam combined

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β-Lactams and β-Lactamase Inhibitors: An Overview

Karen Bush and Patricia A. Bradford

Cold Spring Harb Perspect Med published online June 21, 2016

Subject Collection Antibiotics and Antibiotic Resistance

Fosfomycin: Mechanism and Resistance The Whys and Wherefores of Antibiotic Lynn L. Silver Resistance Cameron R. Strachan and Julian Davies Pleuromutilins: Potent Drugs for Resistant Bugs β-Lactamases: A Focus on Current Challenges −−Mode of Action and Resistance Robert A. Bonomo Susanne Paukner and Rosemarie Riedl Appropriate Targets for Antibacterial Drugs Approved Glycopeptide Antibacterial Drugs: Lynn L. Silver Mechanism of Action and Resistance Daina Zeng, Dmitri Debabov, Theresa L. Hartsell, et al. Lincosamides, Streptogramins, Phenicols, and Mechanism of Action and Resistance to Pleuromutilins: Mode of Action and Mechanisms Daptomycin in Staphylococcus aureus and of Resistance Enterococci Stefan Schwarz, Jianzhong Shen, Kristina Kadlec, William R. Miller, Arnold S. Bayer and Cesar A. et al. Arias Resistance to Macrolide Antibiotics in Public : Alternative Mechanisms of Action and Health Pathogens Resistance Corey Fyfe, Trudy H. Grossman, Kathy Kerstein, et Michael J. Trimble, Patrik Mlynárcik, Milan Kolár, et al. al. Bacterial Protein Synthesis as a Target for Topoisomerase Inhibitors: Fluoroquinolone Antibiotic Inhibition Mechanisms of Action and Resistance Stefan Arenz and Daniel N. Wilson David C. Hooper and George A. Jacoby Antibacterial Antifolates: From Development β-Lactams and β-Lactamase Inhibitors: An through Resistance to the Next Generation Overview Alexavier Estrada, Dennis L. Wright and Amy C. Karen Bush and Patricia A. Bradford Anderson Antibacterial Drug Discovery Targeting the Rifamycins, Alone and in Combination Lipopolysaccharide Biosynthetic Enzyme LpxC David M. Rothstein Alice L. Erwin

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