β-Lactamase inhibitors: a review of the patent literature (2010 – 2013)

1. Introduction

2. Current b-Lactamases

3. b-Lactamase inhibitors and

antibiotic/b-Lactamase

inhibitor combinations

4. Conclusion

5. Expert opinion

Review

b-Lactamase inhibitors: a reviewof the patent literature2010 -- 2013John D BuynakSouthern Methodist University, Department of Chemistry, Dallas, TX, USA

Introduction: New b-lactamases with ever-broadening substrate specificity are

rapidly disseminating globally, thereby threatening the efficacy of our best

b-lactam antibiotics. A potential solution to this problem is the development

of wide-spectrum b-lactamase inhibitors, to be coadministered with existing

and new b-lactams.

Areas covered: This review covers the patent literature in the b-lactamase

inhibitor area roughly from 2010 to 2013, with prior background being

provided in the cases of key inhibitors and antibiotic/inhibitor combinations.

An effort has been made to identify the strong and weak points of each

inhibitor and combination.

Expert opinion: Research in this field has become increasingly diverse, with

several non-b-lactam inhibitor classes now assuming importance. The empha-

sis has been on finding inhibitors of AmpC, the extended-spectrum b-lacta-mases and class A and D carbapenemases that can demonstrate synergy with

antibiotics against resistant Gram-negative pathogens. Progress has been

made. Metallo-b-lactamases (MBL)-mediated resistance, however, represents

an unmet challenge. The author believes that it will be extremely difficult

to generate a selective, commercially viable MBL inhibitor with sufficient

activity against NDM-1 and that alternate design strategies will need to

be employed.

Keywords: AmpC, antibacterial, carbapenemase, extended-spectrum b-lactamase,

Gram-negative, b-lactamase, b-lactamase inhibitor

Expert Opin. Ther. Patents [Early Online]

1. Introduction

Despite decades of searching for new antibacterial targets, b-lactam antibioticsremain firmly entrenched as a mainstay of antimicrobial chemotherapy. This over-reliance has taken its toll, however, with the emergence of b-lactam resistance takingseveral forms: first and foremost, is the production of b-lactamases of ever-broadening substrate specificity; second, are structural alterations of key targettranspeptidase penicillin-binding proteins (PBPs), such as PBP2a of methicillin-resistant Staphylococcus aureus; third and fourth, are the permeability barriers andupregulated efflux of antibiotics employed by Gram-negative strains. When thesefactors are combined, as can be the case with Pseudomonas aeruginosa [1], resistanceis formidable. These challenges, combined with the relatively short administrationtime of antibacterial agents and public expectations that such agents should be inex-pensive, can make antimicrobial drug discovery a forbidding, and potentially non-lucrative, endeavor. The past 15 years has seen a steady exit of major pharmaceuticalcompanies from the field. Fortunately, several small- and mid-sized commercialentities and academic institutions have continued activities in the antibacterialarea and this review will highlight many of these endeavors.

10.1517/13543776.2013.831071 © 2013 Informa UK, Ltd. ISSN 1354-3776, e-ISSN 1744-7674 1All rights reserved: reproduction in whole or in part not permitted

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http://informahealthcare.com/journal/ETP

In recognition of the need to encourage development ofnew antibiotics, the US Congress recently approved the Gen-erating Antibiotic Incentives Now (GAIN) Act of 2011 [2].This legislation extends the period of market exclusivity(beyond existing exclusivity) by 5 years for qualified infectiousdisease products, adding an additional 6 months if the prod-uct is accompanied by a diagnostic test [3]. The bill grants pri-ority review and declares the products eligible for the FDA’sFast Track program [4]. Europe has created Combating Bacte-rial Resistance in Europe as a part of the New Drugs 4 BadBugs program, which is part of the Innovative Medicines Ini-tiative. The purpose of these programs is to provide financialsupport for research and development and to create a networkof industrial and academic experts in Europe that willfoster innovation.An important, and historically validated, mechanism for

countering b-lactamase-mediated resistance is the coadminis-tration of a b-lactam antibiotic and a b-lactamase inhibitor,with the three current commercial inhibitors including clavu-lanic acid, sulbactam and tazobactam. However, with the emer-gence of increasingly wide-spectrum b-lactamases (vide infra),it is clear that better inhibitors will be needed if we are to pre-serve the utility of b-lactam antibiotics. This review will coverthe b-lactamase inhibitor patent literature from 2010 to2013 (May). While it will primarily focus on new inhibitorspatented during this period, it will also describe antibiotic/inhibitor combinations which show promise or are currentlyin clinical trials. New b-lactam antibiotics are not covered,unless they have been combined with b-lactamase inhibitorsto generate combination products.

2. Current b-Lactamases

While the origins of the b-lactamases are ancient [5], it isundeniable that the administration of generations of b-lactam antibiotics has accelerated their evolution. Clinicallyisolated distinct b-lactamase now number > 1300 and are

grouped (Ambler) into four classes A -- D. Classes A, C andD are serine enzymes, while class B are zinc metalloenzymes.Historically, class A b-lactamases were most prominent, andcurrent commercial b-lactamase inhibitors are effectiveagainst many, if not most, class A b-lactamases. Some typesof b-lactam antibiotics could be designed to elude these earlyenzymes, for example, the carbapenems (e.g., imipenem, mer-openem) and third-generation cephalosporins (e.g., cefotax-ime), which are poor substrates for many class A and class Cserine b-lactamases, respectively. The past two decades haveseen the evolution of class A and class D serine carbapene-mases, for example, the Klebsiella pneumoniae carbapene-mases [6] (class A, KPC-2 to KPC-11) and OXA-48 [7]

(class D, oxacillinase) and class A extended-spectrum b-lacta-mases [8] (ESBLs), such as CTX-M (cefotaximase, Munich) [9],with CTX-M-14 and CTX-M-15 now being the most prom-inent ESBLs worldwide [10,11]. Additionally, the genes codingfor class C b-lactamases (AmpC), which were historicallysolely chromosomal, are increasingly found on plasmids,thus facilitating their dissemination [12,13]. ChromosomalampC can be upregulated, leading to hyperexpression [14],and mutations can give AmpC a broader substrate specificity,leading to an extended-spectrum AmpC and contributing toimipenem resistance [15]. Hyperexpression of AmpC inP. aeruginosa, combined with permeability modifications(oprD mutations) and upregulated efflux (overexpression ofMexAB-OprM) can create a highly resistant microorgan-ism [16]. To make matters worse (if that is possible), the classB metallo-b-lactamases (MBLs), just 20 years ago regarded ascuriosities, have now become important resistance factors, themost poignant example being the worldwide dissemination ofthe New Delhi MBL NDM-1 in the past 5 years [17], but alsoincluding the widely disseminated Verona integron-encodedvvMBL (VIM) and active on imipenem (IMP) MBLs, whichhave been circulating in Europe and Asia for the past twodecades [18]. The most problematic b-lactamase-producingpathogens include Enterobacteriaceae [19], P. aeruginosa [20]

and Acinetobacter baumannii [21], and it is these Gram-negative microorganisms that have been the focus ofb-lactamase inhibitor research for the past decade.

3. b-Lactamase inhibitors and antibiotic/b-Lactamase inhibitor combinations

3.1 Antibioticb-Lactamase inhibitor design must necessarily begin with theproper choice of combination b-lactam antibiotic, whoseweak points are then suitably covered by the inhibitor. Owingto the emphasis on Gram-negative pathogens, today’s mostcommonly selected antibiotics include the cephalosporins,ceftolozane, ceftazidime and ceftaroline, the carbapenems imi-penem, doripenem and biapenem and the monobactams,tigemonam, BAL19764 and BAL30072. Structures are shownin Figure 1.

Article highlights.

. The rapid emergence and dissemination of b-lactamasesof increased substrate specificity has stimulated thesearch for improved b-lactamase inhibitors and/orinhibitor--antibiotic combinations.

. The key target b-lactamases include AmpC, ESBLs,classes A and C carbapenemases and MBLs, especially asproduced in Enterobacteriaceae, P. aeruginosa andA. baumannii.

. New classes of b-lactamase inhibitors, of the serineb-lactamases include the DBOs, such as avibactam andboronic acid inhibitors.

. Progress is less rapid on MBL inhibitors, especially ondevising effective inhibitors of NDM-1.

This box summarizes key points contained in the article.

J. D. Buynak

2 Expert Opin. Ther. Patents (2013) 23(11)

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3.2 Current commercial b-lactamase inhibitorsIn addition to discovering new b-lactamase inhibitors, oneapproach to developing a new antibiotic/inhibitor combina-tion is to pair an existing b-lactamase inhibitor togetherwith a new antibiotic (e.g., ceftolozane/tazobactam, vide infra).It is, therefore, appropriate to list the existing b-lactamaseinhibitors, clavulanic acid, sulbactam and tazobactam, withstructures shown in Figure 2. Currently available b-lactamaseinhibitors are effectively limited to many class A b-lactamases,excluding the KPC carbapenemases.

3.3 b-lactamase inhibitors and antibiotic--inhibitor

combinations in development3.3.1 Ceftolozane--tazobactamCubist is currently developing ceftolozane (Figure 1), an anti-pseudomonal cephalosporin antibiotic, in combination withthe b-lactamase inhibitor tazobactam (Figure 2), as an intrave-nous agent to treat serious infections caused by Gram-negativemicroorganisms, especially including those involving P.

aeruginosa. Ceftolozane was originally discovered by Fujisawa(initially known as FR264205) in 2004 [22,23]. Early studiesindicate that ceftolozane MICs against clinical P. aeruginosa iso-lates are 8- to 16-fold lower than those of ceftazidime, and showlittle effect from MexAB-OprM overexpression and/or OprDdeletion, but ceftolozane was susceptible to ESBL production,with MICs for ESBL producers being increased by 4- to128-fold [24]. Independent studies confirmed the improved anti-pseudomonal activity of ceftolozane, with MICs being 2- to16-fold lower than those of ceftazidime against multidrug resis-tant P. aeruginosa [25,26]. After Fujisawa merged with Yamanou-chi in 2005, the rights for ceftolozane were acquired by CalixaTherapeutics, and ceftolozane became known as CXA-101,and the ceftolozane--tazobactam combination as CXA-201.Clinical trials were initiated. Cubist acquired Calixa in2009 and still continues to develop the ceftolozane/tazobactamcombination and has recently filed a patent covering the useof a 2:1 ratio of ceftolozane/tazobactam to treat intrapulmonaryinfections [27]. Independent studies in Enterobacteriaceaeconfirm that ceftolozane has vulnerabilities against isolates

N

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CO2-

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NH2

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Ceftolozane sulfate (CXA-101, FR264205)

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Ceftaroline fosamil monoacetate

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Imipenem

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Tigemonam dicholine

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BAL19764, sodium salt

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OH

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CH3CO2-

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NH2N

Me

OSO3Na

BAL30072, sodium salt

N

O

OH

OH

Me

Figure 1. Schematic representation of the structures of b-Lactam antibiotics being investigated in combination with

b-lactamase inhibitors.

b-lactamase inhibitors: a review of the patent literature 2010 -- 2013

Expert Opin. Ther. Patents (2013) 23 (11) 3

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producing ESBLs, AmpC overproducers and KPC carbapene-mases which can be partially rectified by the addition of tazobac-tam [28]. The addition of tazobactam at 8 µg/ml resulted inrestoring the susceptibility of 93% of the ESBL producers and95% of the AmpC overproducers. Tazobactam was unable tolower MICs, however, for Enterobacteriaceae producing KPCcarbapenemases [28]. Other studies confirm the value of ceftolo-zane alone (and in combination with tazobactam) as an antipseu-domonal agent, including against imipenem-resistant strains.The addition of the inhibitor does not seem to reduce alreadygood P. aeruginosa MICs but does serve to reduce MICs againstESBL-producing Enterobacteriaceae [29,30]. CXA-201 is currentlyinvolved in Phase III clinical trials as intravenous therapy forcomplicated intra-abdominal infections (cIAI), with intravenousmeropenem as comparator [31] and as intravenous therapy forcomplicated urinary tract infections (cUTI), including pyelone-phritis, with levofloxacin as comparator [32].

3.3.2 AzabicyclicsThe bridged 1,6-diazabicyclo[3.2.1]ocatan-7-ones (DBOs,Figure 3) were conceived as potential b-lactam analogs by chem-ists at Hoechst Marion Roussel (HMR) in the mid-1990s [33].Early examples lacked antibacterial activity, but could inhibitclasses A and C b-lactamases. In 1999, HMR merged with theFrench company Rhone-Poulenc S.A. to form Aventis. The ini-tial patents were filed in 2001 -- 2004 [34-37] and the structureselected for development became known as AVE1330A [38]. In2004, Aventis was taken over by Sanofi-Synthelabo to formSanofi-Aventis, and Novexel was formed as a spin-out of theanti-infectives unit, with the compound now becomingNXL104. Forest Laboratories began developing combination

products of NXL104 with the anti-MRSA fifth-generationcephalosporin, ceftaroline fosamil, to treat Gram-positivepathogens and with ceftazidime for Gram-negative pathogens.After AstraZeneca acquired Novexel in 2010, the compoundbecame known as avibactam. Cerexa, Inc., a wholly-ownedsubsidiary of Forest Laboratories, continues to develop theceftaroline fosamil-- avibactam combination, while AstraZenecaand Forest collaboratively develop the ceftazidime--avibactam(CAZ-AVI or CAZ104) combination.

Avibactam has an extremely broad spectrum of activityagainst classes A and C serine b-lactamases [38], includingESBLs and class A carbapenemases [39,40]. This moleculeinhibits selected class D b-lactamases including OXA-48,but apparently not other class D carbapenemases, as judgedby the absence of synergy with imipenem against resistantstrains of A. baumannii producing OXA-51 andOXA-58 [41] and does not inhibit class B MBLs. Avibactam,thus, represents a significant improvement over current com-mercial b-lactamase inhibitors, which are effectively limited tothe inhibition of class A enzymes and do not demonstrateappreciable potency against the class A KPC carbapenemases.Mechanistically, avibactam is characterized as a covalent, butslowly reversible, non-b-lactam b-lactamase inhibitor, a previ-ously unknown class. The acyl-enzyme, a carbamate, is stabi-lized toward hydrolysis but can slowly recyclize to intactavibactam, simultaneously releasing the active enzyme [42].

Avibactam can greatly lower MICs (4- to 1024-fold),restoring susceptibility of resistant Enterobacteriaceae as docu-mented by the following studies. Avibactam was combinedwith: i) ceftazidime against Enterobacteriaceae producing classA and class C b-lactamases [38]; ii) piperacillin, cefotaxime,

N

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OCO2K

Clavulanic acid, potassium salt

OH

N

O2S

OCO2Na

Sulbactam, sodium salt

N

O2S

OCO2Na

Tazobactam, sodium salt

N NN

Figure 2. Schematic representation of the current commercial b-lactamase inhibitors.

N

N

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OSO3Na

Avibactam sodium

N

N

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MK-7655

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OCH2CO2Na

Novexel WO 2009133442

N

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O OSO3Na

Wockhardt Ltd. WO 2013038330

Figure 3. Schematic representation of 1,6-Diazabicyclo[3.2.1]ocatan-7-ones (DBOs) b-lactamase inhibitors.

J. D. Buynak


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ceftazidime, cefepime or aztreonam against KPC-producingisolates of K. pneumoniae [43]; iii) cefotaxime or ceftazidimeagainst Enterobacteriaceae producing CTX-M ESBLs [44];iv) ceftazidime, ceftriaxone, imipenem or piperacillin againstKPC-2 producing strains of Enterobacteriaceae [40];v) ceftaroline against Enterobacteriaceae producing ESBLs [45];vi) ceftaroline against ESBL- and serine carbapenemase-producing Enterobacteriaceae [46,47]; vii) imipenem, cefepimeor ceftazidime against OXA-48 producing and CTX-Mproducing K. pneumoniae and Escherichia coli [41]. Avibactamhas ability to reduce the MICs of ceftazidime (2- to 16-fold)against AmpC derepressed mutants of P. aeruginosa andagainst P. aeruginosa mutants producing the class A PER-1ESBL. This inhibitor is not effective against P. aeruginosastrains with OXA ESBLs or the VEB-1 enzyme [41,46,48,49,47,50].Avibactam has no ability to reduce MICs of ceftazidimeagainst carbapenem-resistant A. baumannii [48,47,41].

Avibactam demonstrated synergy with ceftaroline againstselected b-lactamase-producing anaerobic strains, Bacteroidesfragilis, Prevotella spp. and Finegoldia magna cultured fromdiabetic foot infections [51]. The antistaphylococcal cephalo-sporin ceftaroline is a good partner antibiotic, since S. aureus(including MRSA) is a dominant aerobic pathogen [52] in the,often mixed aerobic/anaerobic [53], diabetic foot infections.Ceftaroline has some inherent anaerobic activity but is inef-fective (as monotherapy) against b-lactamase producingGram-negative anaerobic strains, including B. fragilis [54,55].By contrast, the avibactam--ceftazidime combination hadvery modest activity against anaerobes [56]. When CAZ-AVI wascombined with metronidazole, however, the MICs were substan-tially lower for many Gram-negative anaerobes, and thus the tri-ple combination may have utility in treating mixed infectionsinvolving aerobic/anaerobic microorganisms, particularly includ-ing resistant Enterobacteriaceae and anaerobes [56,57], which arecommon in intra-abdominal infections [58].

Numerous clinical trials involving avibactam have been com-pleted and are in progress. A 125/500 mg t.i.d. combination ofavibactam/ceftazidime has completed a Phase II clinical trial forthe treatment of cUTI using imipenem/cilastatin as compara-tor [59]. A triple combination of ceftazidime, avibactam andmetronidazole has completed a Phase II clinical trial for intra-venous treatment of cIAI using meropenem as comparator [60]

with results indicating similar efficacy of the triple combinationas compared to meropenem alone [61]. A Phase I safety, tolera-bility and pharmacokinetic study of avibactam alone and a4:1 combination of ceftazidime/avibactam has been com-pleted [62]. A Phase I study of the effect of 2000 mg avibactam +1500 mg ceftaroline combination and a 2000 mg avibactam +3000 mg ceftazidime combination on QT/QTc interval hasbeen completed [63]. A Phase I study to evaluate the concentra-tions of two different avibactam/ceftazidime mixtures on con-centrations in epithelial lining fluid and plasma has beencompleted [64]. A Phase I pharmacokinetic and drug--druginteraction study of avibactam/ceftazidime mixtures has beencompleted [65]. A 1:1 combination of avibactam with

ceftaroline fosamil has completed a Phase II clinical trial as atreatment for cUTI using doripenem as comparator [66].A Phase I trial mass balance recovery, metabolite profile andmetabolite identification of [14C]avibactam has been com-pleted [67]. AstraZeneca has patented a process for the prepara-tion of DBOs, including avibactam [68].

Subsequent to the discovery of avibactam, Merck patentedMK-7655, a new member of the DBO series [69], and a processfor its preparation [70,71]. A combination of imipenem andMK-7655 has excellent activity against a KPC-2-producing iso-late of K. pneumoniae and displays moderate improvements inthe imipenem efficacy against most AmpC-overexpressingisolates of P. aeruginosa. [72]. MK-7655 has completed aPhase I clinical trial in combination with imipenem--cilastatinto evaluate the pharmacokinetics in individuals with impairedrenal function [73]. This inhibitor is currently involved intwo Phase II clinical trials studying the safety, tolerability andefficacy of combinations of 125 and 250 mg of MK-7655with 500 mg imipenem--cilastatin in treating cUTI [74] orcIAI [75].

Structurally related DBOs have recently been patented asb-lactamase inhibitors (e.g., WO2009133442) [76,77]. Wock-hard Ltd reports a DBO nitrile (Figure 3) with inhibitoryactivity equivalent to avibactam but also exhibits synergywith meropenem against class D ESBL producing strains ofA. baumannii [78]. A patent regarding the use of DBOs asdiagnostic agents has appeared [79] as has a patent of novelcrystalline forms of avibactam [80]. Patents have appearedinvolving the preparation of chiral avibactam and chiralintermediates useful therein [81,82].

In an important development, derivative DBOs havingindependent antibacterial activity against P. aeruginosa and/orE. coli have been patented and are shown in Figure 4 [83-88].

3.3.3 Boronic acid-based b-lactamase inhibitorsBoronic acid-based b-lactamase inhibitors were first reportedin 1978 [89], and these were gradually improved to mimicthe structures of the natural b-lactamase substrates [90].A patent involving boronic acid inhibitors designed to struc-turally mimic the penicillin side chain was filed in 2007 [91].These have gradually increased in sophistication as shownin Figure 5 [92]. The cyclic boronates (i.e., 1,5,2-dioxabore-pane-2-ols) were shown to lower the MIC of tigemonamagainst class A ESBLs as well as C- and D-producing strainsof E. coli and K. pneumoniae [93]. Cyclic boronateRPX7009 [94] is being developed in combination with biape-nem. A recent publication shows good synergy of this cyclicboronate with biapenem against KPC-producing Enterobac-teriaceae, with inhibitor concentrations as low as 2 µg/ml,reducing the MICs of biapenem to £ 1 µg/ml for over 90%of the isolates [95]. Phase I clinical trials are evaluating thesafety, tolerability and pharmacokinetics of RPX7009 [96]

and the safety of biapenem and RPX7009 alone and incombination [97]. Sulfonamido boronic acids have beenpatented [98]. Initial studies showed that sulfonamide boronic



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acid inhibitors can reduce the MIC of ceftazidime by 4- to16-fold against b-lactamase producing Gram-negative strains,including P. aeruginosa [99]. Further refinement using afragment-based approach led to the tetrazole shown, whichcan lower MICs in AmpC-overproducing E. coli by as muchas 256-fold and shows efficacy in a murine model [100]. Last,a library of triazole-substituted boronic acids was generatedusing a ‘click chemistry’ approach and selected boronic acidswere shown to have ability to inhibit class A and class C b-lactamases, including the KPC-2 carbapenemase, and todisplay synergy with ampicillin against several strains ofb-lactamase producing E. coli [101].

3.3.4 Bridged monocyclic-b-lactamsMonobactam antibiotics, such as aztreonam, are knowninhibitors of AmpC b-lactamases [102]. Bridged monobactams(e.g., Ro48-1256, Figure 6) are particularly potent AmpCinhibitors which were structurally optimized by workers atHoffmann-La Roche in 1998 [103]. While no new patentshave appeared in this area in the past 3 years, Basilea and

Merck have continued to report developments in the scientificliterature. Basilea has developed b-lactamase inhibitorBAL29880 [104], in a triple combination with the antibioticmonobactam-siderophore BAL19764 [105] and commercialb-lactamase inhibitor clavulanic acid to generate a productknown as BAL30376 [106]. This strategy is for BAL19764to function as an MBL-resistant monobactam antibiotic,BAL29880, to protect BAL19764 by inhibiting AmpC, andclavulanic acid to inhibit remaining class A b-lactamases,including ESBLs [107,108]. A recent study showed that thisstrategy does succeed for the majority (~ 85%) of strains pos-sessing resistance due to MBL, AmpC or ESBL production,but does not succeed for KPC carbapenemase producers andfor many P. aeruginosa isolates obtained from cystic fibrosispatients [109]. A similar strategy was employed for the mono-sulfactam BAL30072 (Figure 1), which exhibited potent activ-ity against Acinetobacter spp. and P. aeruginosa [110]. Additionof BAL29880 and clavulanic acid had similar effects, improv-ing susceptibility of resistant Enterobacteriaceae [111]. Merckreports that the bridged monobactam MK-8712 [112] has

N

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WO 2010038115, Novexel

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WO 2013030733, Wockhardt Ltd.

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WO 2013030735, Wockhardt Ltd.

NN

OH3C

Figure 4. Schematic representation of DBOs with antibacterial activity.

B

HN

OHHOO

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Shoichet, Prati US 7271186

HN

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HOB

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Burns et al. US 20100120715

B O

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Rempex WO 2013033461

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NN

Shoichet et al. WO 2013056163

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Therabor WO 2013053372

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CO2H

Rempex WO 2012021455 (RPX7009)

Figure 5. Schematic representation of boronic acid-based b-lactamase inhibitors.

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better AmpC inhibitory activity and synergy with imipenemthan the Roche compound Ro48-1256 but it terminateddevelopment due to ‘inadequate therapeutic margin in subse-quent safety studies’ [113]. Subsequent investigations onN-substituted analogs of this molecule identified more potentAmpC inhibitors but failed to find compounds whichexhibited superior synergy with imipenem [114].

3.3.5 Miscellaneous inhibitors of serine b-lactamasesMobashery et al. have patented a series of phthalanilate com-pounds (Figure 7), members of which have antimicrobial and/or b-lactamase inhibitory activity [115]. More than 400 such com-pounds were synthesized and evaluated for b-lactamase inhibi-tory activity against classes A, C and D serine b-lactamases(TEM-1, P99 and OXA-10) as well as the binding to the Staph-ylococcal penicillin-sensing protein, BlaR1, and to the MRSAlow-b-lactam affinity protein PBP2a. The best inhibitors weresubmicromolar against all three representative serine b-lacta-mases. The best antibiotics had activity against Gram-positivestrains, including MRSA (MICs = 4 -- 16 µg/ml).

Mansour and Venkatesan , when at Wyeth (now part ofPfizer), patented 6-methylidene carbapenems as broad-spectrum inhibitors [116]. Data are provided for one (unspeci-fied) compound in this series, which has IC50 values of 80 nMagainst TEM-1 and 120 nM against AmpC. Lek Pharmaceut-icals has patented a series of tricyclic carbapenems (trinems)which possess both antibiotic activity as well as b-lactamaseinhibitory activity, with the best compound showing IC50sagainst TEM-1, SHV-1 and P99 of 0.5, 0.012 and0.0005 µM, respectively [117,118]. This same compound(LK-180) demonstrates antibiotic activity superior to that ofpiperacillin/tazobactam against AmpC-producing Gram-neg-ative strains, but was less active against a Citrobacter freundiistrain producing the CTX-M ESBL. Naeja Pharmaceuticalshas recently patented a new 6-alkylidene penem as ab-lactamase inhibitor but no data on its efficacy are pro-vided [119]. Orchid Research Laboratories has patentedzwitterionic penicillin sulfones which are modest inhibitorsof the carbapenemases KPC-2 and KPC-3 (IC50 = 190 and10.7 µM, respectively), but which show good synergy, whencombined with imipenem (and several other b-lactam antibi-otics), in treatment of carbapenemase-producing strains ofK. pneumoniae, Enterobacter cloacae and E. coli [120]. NabrivaTherapeutics has patented substituted clavams which inhibitAmpC, SHV-1 and TEM-1 at concentrations of 6.1,

0.0026 and 0.0018 µM, respectively [121]. These clavams syn-ergize with ceftazidime and cefepime against resistant strainsof K. pneumoniae, E. cloacae and C. freundii. Buynak et al.has patented a series of 2¢-substituted-6-alkylidene penicillinsulfones, which are potent inhibitors of representativeclasses A, C and D b-lactamases (IC50 against TEM-1,KPC-3, AmpC and OXA-24/40 at 0.0001, 28.2, 0.039 and0.079 µM, respectively) and which synergize with imipenemagainst resistant strains of P. aeruginosa, K. pneumoniae andA. baumannii [122,123].

3.3.6 MBL inhibitorsWith the increasing prevalence of MBL-mediated resistance,particularly including NDM-1-producing strains, there isrenewed interest in the design of MBL inhibitors. Substitutedmaleic acid derivatives (Figure 8) were patented as MBL inhib-itors in 2007 [124,125]. These maleic acid derivatives can havevarying inhibitory activity, depending on the nature of R1

and R2, with somewhat larger groups (e.g., benzyl) showingbetter MBL inhibitory potency against the MBLs IMP-1and VIM-2 in biochemical assays [125]. Despite theirimproved inhibitory potency, however, those larger maleicacid analogs did not lower MICs of partner antibiotics againstan MBL-producing P. aeruginosa strain as much as the diso-dium salt of 2,3-diethylmaleic acid, R1 = R2 = Et [125]. Thiscompound has been named ME1071, and a recent articledescribes more thorough evaluation of ME1071, combinedat 32 µg/ml, with piperacillin, ceftazidime, aztreonam, imipe-nem, meropenem, biapenem or doripenem against IMP-1- orVIM-2-producing strains of P. aeruginosa [126]. Synergy wasobserved with ceftazidime and with the carbapenems. TheMIC50 of biapenem against IMP-1-producing P. aeruginosabeing lowered by > 8-fold, and the susceptibility of VIM-2-producing P. aeruginosa to ceftazidime was increased by38%. A recent study indicates that ME1071 is less effectiveat reducing the MICs of representative carbapenems againstEnterobacteriaceae and Acinetobacter spp. producingNDM-1 with 32 µg/ml of the inhibitor generating only a2.6-fold lowering of the mean MIC and 10-fold potentiationwas not achieved even at 128 µg/ml [127]. Again, biapenemwas identified as the best companion antibiotic, based on itshigher degree of synergy with the inhibitor and its lower affin-ity for the MBLs than other carbapenems. A recent patentdescribes the preparation of maleic acid derivatives withimproved ability to inhibit NDM-1 and to synergize with

N

N

O SO3-

NH

OH2N+

Ro48-1256

N

N

O SO3-

NH

O

BAL29880

HNH

N

O

H3N+N

N

O SO3-

NH

OH3N+

MK-8712

Figure 6. Schematic representation of bridged monocyclic b-lactamase inhibitors.



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imipenem [128]. Maleic acid derivatives have also been pat-ented for their use in a method of distinguishing betweenIMP- and VIM-producing bacteria [129].Isatin-derived thiosemicarbazones have recently been pat-

ented as NDM-1 inhibitors [130]. Substituted dihydrothiazolecarboxylic acids have been patented as MBL inhibitors [131],with the best compound having an IC50 of 5.5 µM againstIMP-1 and no appreciable activity against Bla2 of Bacillus

anthracis. No data are reported on VIM-2 or NDM-1 [132].Last, 3¢-thiobenzoyl cephalosporin derivatives have been pat-ented as dual MBL/serine b-lactamase inhibitors [133]. Thesecompounds were designed a mechanism-based inhibitorsthat would release the inhibitory thiobenzoic acid whenhydrolyzed. Interestingly, these compounds exhibit not onlyinhibition of the MBLs IMP-1 (3.1 µM), VIM-2 (1.8 µM)and NDM-1 (33 µM) but also low level inhibition of

O

HN

ClCl

Cl

Cl CO2H

O (CH2)n CH3

n = 7 or 15

Mobashery et al. WO 2011026107

N

NH+

NS

OCO2

-

Mansour et al.US 20100063023

NO

CO2Na

OCH3

OH

FCH2

Lek Pharmaceuticals WO 2009153297

N

S

N

N

OCO2H

Me

Naeja Pharmaceuticals Inc.US 20110288063

N

O2S

OCO2

-

N N+ Me

Orchic Laboratories WO 2012070071

N

O

OCO2H

O

O

Nabriva Therapeutics WO 2011032192

N

O2S

OCO2

-

OCONH2

N

NH3+

Buynak et al. US 20100009954

Figure 7. Schematic representation of miscellaneous inhibitors of serine b-lactamases.

NaO2C

R1 R2

CO2Na

Meiji Seika Kaisha Ltd. WO 2007034924 ME1071: R1 = R2 = Et

NaO2C CO2Na

OH

O

H2N

Meiji Seika Kaisha Ltd. WO 2013015388

NH

O

N NH

HN

S

I

Guo et al. CN 102626408

N

S

CO2H

Horton et al. WO 2012088283

N

S

OCO2H

S

O

HN

O

S

Dmitrienko et al. WO 2011103686

Figure 8. Schematic representation of MBL inhibitors.

J. D. Buynak


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KPC-2 (71 µM) and the class D OXA-10 (8.1 µM) andOXA-45 (24 µM). However, significant synergy with mero-penem against selected strains of P. aeruginosa, Stenotrophomo-nas maltophilia and Chryseobacterium meningosepticum is onlyobserved at the relatively high concentration of 100 µg/ml [133]. A single-stranded DNA aptamer has recently beenpatented for the use of detecting NDM-1 [134].

4. Conclusion

The rapid and widespread dissemination of b-lactamases ofever-increasing substrate specificity in Gram-negative micro-organisms represents a frightening scenario for the clinician.Judging by the wide array of structural subtypes currentlyunder exploration, medicinal chemists are rising to the chal-lenge. Barring the unmet problem of the MBLs, many ofthe compound classes described herein have broader inhibi-tory spectrum than existing inhibitors and can inactivate oneor more of the problematic enzymes, including AmpC, theESBLs, the KPC carbapenemases and/or the class D carbape-nemases. It is also encouraging that some of the compoundclasses are unaffected by permeability barriers and efflux.The emphasis has been on finding/developing inhibitorsof the serine b-lactamases, and this effort has beenpartially successful.

5. Expert opinion

The most important finding of the recent patent literature inthis area is that non-b-lactams (i.e., the DBOs and theboronic acids) can serve as inhibitors of serine-b-lactamasesnot targeted by current commercial inhibitors, particularly

including AmpC and the KPC carbapenemases. While no sin-gle inhibitor has ideal characteristics, these new classes repre-sent a substantial improvement over existing commercialinhibitors. Avibactam is advancing rapidly in numerous clin-ical trials, and the other DBO, MK7655, is also progressinginto Phase II trials. Only one boronic acid, RPX7009, is inPhase I trials. The next major challenge will be MBL-mediated resistance. The rapid global dissemination ofNDM-1 has caught the antibiotic community by surpriseand we have, as yet, no real answer. MBL inhibitors identifiedto date are relatively ineffective against NDM-1. The authorbelieves that it is likely impossible to generate a selective, com-mercially viable MBL inhibitor with sufficient activity againstNDM-1. A better strategy may be to generate a dual serine/MBL inhibitor or an antibiotic which is a very poor substratefor MBLs (e.g., monobactams), to couple with an inhibitor ofthe serine-b-lactamases. Hopefully, the diversity of structuresfound herein represents only the tip of the iceberg of potentialmolecular classes that may target the general class ofpenicillin-recognizing enzymes (i.e., b-lactamases and PBPs),and can thus be an encouragement to those wishing to enterthis research field. Clearly, these enzymes represent very valu-able, and usually accessible, antibiotic targets. As we progressinto an era of increased global travel and population density,and more widespread antibiotic use, it is paramount that wemaintain research programs in the antimicrobial fields.

Declaration of interest

JD Buynak has no current support from any of the companiesmentioned herein.

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AffiliationJohn D Buynak

Southern Methodist University,

Department of Chemistry,

Dallas, TX 75275, USA

E-mail: [email protected]



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β-Lactamase inhibitors: a review of the patent literature (2010 – 2013)

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