Skip to main content
SpringerLink
Log in

Recent advances in the development of β-lactamase inhibitors

  • Minireview
  • Published:
Journal of Microbiology Aims and scope Submit manuscript

Abstract

β-Lactam antibiotics are the most commonly prescribed antibiotics worldwide; however, antimicrobial resistance (AMR) is a global challenge. The β-lactam resistance in Gram-negative bacteria is due to the production of β-lactamases, including extended-spectrum β-lactamases, metallo-β-lactamases, and carbapenem-hydrolyzing class D β-lactamases. To restore the efficacy of BLAs, the most successful strategy is to use them in combination with β-lactamase inhibitors (BLI). Here we review the medically relevant β-lactamase families and penicillins, diazabicyclooctanes, boronic acids, and novel chemical scaffold-based BLIs, in particular approved and under clinical development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Aboklaish, A.F., Okujava, R., El-Bouseary, M., Zampaloni, C., Najera, I., Bradley, K., Walsh, T.R., and Tyrrell, J.M. 2018. Nacubactam antibacterial activity alone and in combination with β-lactam antibiotics against contemporary Enterobacteriaceae clinical isolates. European Congress of Clinical Microbiology and Infectious Diseases (28th ECCMID) Madrid Spain, Abs. P1034.

    Google Scholar 

  • Aktaş, Z., Kayacan, C., and Oncul, O. 2012. In vitro activity of avibactam (NXL104) in combination with β-lactams against Gram-negative bacteria, including OXA-48 β-lactamase-producing Klebsiella pneumoniae. Int. J. Antimicrob. Agents39, 86–89.

    PubMed  Google Scholar 

  • Alvarez, M., Tran, J.H., Chow, N., and Jacoby, G.A. 2004. Epidemiology of conjugative plasmid-mediated AmpC β-lactamases in the United States. Antimicrob. Agents Chemother.48, 533–537.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ambler, R.P. 1980. The structure of β-lactamases. Philos. Trans. R. Soc. Lond. B Biol. Sci.289, 321–331.

    CAS  PubMed  Google Scholar 

  • Bebrone, C. 2007. Metallo-β-lactamases (Classification, activity, genetic organization, structure, Zinc coordination) and their superfamily. Biochem. Pharmacol.74, 1686–1701.

    CAS  PubMed  Google Scholar 

  • Beck, J., Sauvage, E., Charlier, P., and Marchand-Brynaert, J. 2008. 2-Aminopropane-1, 2, 3-tricarboxylic acid: synthesis and co-crystallization with the class A β-lactamase BS3 of Bacillus licheniformis. Bioorg. Med. Chem. Lett.18, 3764–3768.

    CAS  PubMed  Google Scholar 

  • Biedenbach, D.J., Kazmierczak, K., Bouchillon, S.K., Sahm, D.F., and Bradford, P.A. 2015. In vitro activity of Aztreonam-Avibactam against a global collection of Gram-negative pathogens from 2012 and 2013. Antimicrob. Agents Chemother.59, 4239–4248.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bonomo, R.A. and Szabo, D. 2006. Mechanisms of multidrug resistance in Acinetobacter species and Pseudomonas aeruginosa. Clin. Infect. Dis.43, S49–S56.

    CAS  PubMed  Google Scholar 

  • Brem, J., van Berkel, S.S., Aik, W., Rydzik, A.M., Avison, M.B., Pettinati I., Umland, K.D., Kawamura, A., Spencer, J., Claridge, T.D.W., et al. 2014. Rhodanine hydrolysis leads to potent thioenolate mediated metallo-β-lactamase inhibition. Nat. Chem.6, 1084–1090.

    CAS  PubMed  Google Scholar 

  • Brem, J., van Berkel, S.S., Zollman, D., Lee, S.Y., Gileadi, O., McHugh, P.J., Walsh, T.R., McDonough, M.A., and Schofield, C.J. 2016. Structural basis of metallo-β-lactamase inhibition by captopril stereoisomers. Antimicrob. Agents Chemother.60, 142–150.

    CAS  PubMed  Google Scholar 

  • Burns, C.J., Daigle, D., Liu, B., Jackson, R.W., Hamrick, J., McGarry, D., Pevear, D.C., and Trout, R.E.L. 2017. β-Lactamase inhibitors. US Patent 9637504 B2, Venatorx Pharmaceuticals Inc., Philadelphia, USA.

    Google Scholar 

  • Bush, K. 2018. Past and present perspectives on β-lactamases. Antimicrob. Agents Chemother.62, e01076–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bush, K. and Bradford, P.A. 2019. Interplay between β-lactamases and new β-lactamases inhibitors. Nat. Rev. Microbiol.17, 295–306.

    CAS  PubMed  Google Scholar 

  • Bush, K. and Jacoby, G.A. 2010. Updated functional classification of β-lactamases. Antimicrob. Agents Chemother.54, 969–976.

    CAS  PubMed  Google Scholar 

  • Bush, K., Jacoby, G.A., and Medeiros, A.A. 1995. A functional classification scheme for β-lactamases and its correlation with molecular structure. Antimicrob. Agents Chemother.39, 1211–1233.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bush, K., Macalintal, C., Rasmussen, B.A., Lee, V.J., and Yang, Y. 1993. Kinetic interactions of tazobactam with β-lactamases from all major structural classes. Antimicrob. Agents Chemother.37, 851–858.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cahill, S.T., Cain, R., Wang, D.Y., Lohans, C.T., Wareham, D.W., Oswin, H.P., Mohammed, J., Spencer, J., Fishwick, C.W.G., Mc-Donough, M.A., et al. 2017. Cyclic boronates inhibit all classes of β-lactamases. Antimicrob. Agents Chemother.61, e02260–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen, A.Y., Thomas, P.W., Stewart, A.C., Bergstrom, A., Cheng, Z., Miller, C., Bethel, C.R., Marshall, S.H., Credille, C.V., Riley, C.L., et al. 2017. Dipicolinic acid derivatives as inhibitors of New Delhi metallo-β-lactamase-1. J. Med. Chem.60, 7267–7283.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Citron, D.M., Tyrrell, K.L., Merriam, V., and Goldstein, E.J.C. 2011. In vitro activity of Ceftazidime-NXL104 against 396 strains of β-lactamase-producing anaerobes. Antimicrob. Agents Chemother.55, 3616–3620.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cluck, D., Lewis, P., Stayer, B., Spivey, J., and Moorman, J. 2015. Ceftolozane-tazobactam: a new-generation cephalosporin. Am. J. Health Syst. Pharm.72, 2135–2146.

    CAS  PubMed  Google Scholar 

  • Coleman, K. 2011. Diazabicyclooctanes (DBOs): a potent new class of non-β-lactam β-lactamase inhibitors. Curr. Opin. Microbiol.14, 550–555.

    CAS  PubMed  Google Scholar 

  • Day, J.A. and Cohen, S.M. 2013. Investigating the selectivity of metalloenzyme inhibitors. J. Med. Chem.56, 7997–8007.

    CAS  PubMed  Google Scholar 

  • Dever, L.A. and Dermody, T.S. 1991. Mechanisms of bacterial resistance to antibiotics. Arch. Intern. Med.151, 886–895.

    CAS  PubMed  Google Scholar 

  • Dhillon, S. 2018. Meropenem/Vaborbactam: a review in complicated urinary tract infections. Drugs78, 1259–1270.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Doi, Y. 2019. Treatment options for carbapenem-resistant Gram-negative bacterial infections. Clin. Infect. Dis.69, S565–S575.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Drawz, S.M., Bethel, C.R., Doppalapudi, V.R., Sheri, A., Pagadala, S.R.R., Hujer, A.M., Skalweit, M.J., Anderson, V.E., Chen, S.G., Buynak, J.D., et al. 2010. Penicillin sulfone inhibitors of class D β-lactamases. Antimicrob. Agents Chemother.54, 1414–1424.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Drawz, S.M. and Bonomo, R.A. 2010. Three decades of β-lactamase inhibitors. Clin. Microbiol. Rev.23, 160–201.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Drawz, S.M., Papp-Wallace, K.M., and Bonomo, R.A. 2014. New β-lactamase inhibitors: a therapeutic renaissance in an MDR world. Antimicrob. Agents Chemother.58, 1835–1846.

    PubMed  PubMed Central  Google Scholar 

  • Duin, D.V. and Bonomo, R.A. 2016. Ceftazidime/Avibactam and Ceftolozane/Tazobactam: second-generation β-lactam/β-lactamase inhibitor combinations. Clin. Infect. Dis.63, 234–241.

    PubMed  PubMed Central  Google Scholar 

  • Duin, D.V. and Paterson, D. 2016. Multidrug-resistant bacteria in the community: trends and lessons learned. Infect. Dis. Clin. North Am.30, 377–390.

    PubMed  PubMed Central  Google Scholar 

  • Durand-Réville, T.F., Guler, S., Comita-Prevoir, J., Chen, B., Bifulco, N., Huynh, H., Lahiri, S., Shapiro, A.B., McLeod, S.M., Carter, N.M., et al. 2017. ETX2514 is a broad-spectrum β-lactamase inhibitor for the treatment of drug-resistant Gram-negative bacteria including Acinetobacter baumannii. Nat. Microbiol.2, 17104.

    PubMed  Google Scholar 

  • Ehmann, D.E., Jahic, H., Ross, P.L., Gu, R.F., Hu, J., Durand-Réville, T.F., Lahiri, S., Thresher, J., Livchak, S., Gao, N., et al. 2013. Kinetics of Avibactam inhibition against Class A, C, and D β-lactamases. J. Biol. Chem.288, 27960–27971.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Giacobbe, D.R., Bassetti, M., De Rosa, F.G., Del Bono, V., Grossi, P.A., Menichetti, F., Pea, F., Rossolini, G.M., Tumbarello, M., Viale, P., et al. 2018. Ceftolozane/tazobactam: place in therapy. Expert Rev. Anti. Infext. Ther.16, 307–320.

    CAS  Google Scholar 

  • Gin, A., Dilay, L., Karlowsky, J.A., Walkty, A., Rubinstein, E., and Zhanel, G.G. 2007. Piperacillin-tazobactam: a β-lactam/β-lactamase inhibitor combination. Expert Rev. Anti. Infect. Ther.5, 365–383.

    CAS  PubMed  Google Scholar 

  • González-Bello, C. 2017. Antibiotic adjuvants-a strategy to unlock bacterial resistance to antibiotics. Bioorg. Med. Chem. Lett.27, 4221–4228.

    PubMed  Google Scholar 

  • González-Bello, C., Rodríguez, D., Pernas, M., Rodríguez, A., and Colchón, E. 2020. β-Lactamase inhibitors to restore the efficacy of antibiotics against superbugs. J. Med. Chem.63, 1859–1881.

    PubMed  Google Scholar 

  • Gordon, E., Duncton, M., Lal, R., and Trias, J. 2019. Oral prodrugs of avibactam, medicinal chemistry, and synthesis of ARX1796. European Congress of Clinical Microbiology and Infectious Diseases (29th ECCMID), Amsterdam, Netherlands. Poster P1159.

    Google Scholar 

  • Haider, G., Clancy, C.J., Chen, L., Samanta, P., Shields, R.K., Kreiswirth, B.N., Nguyen, M.H. 2017. Identifying spectra of activity and therapeutic niches for ceftazidime-avibactam and imipenem-relebactam against carbapenem-resistant Enterobacteriaceae. Antimicrob. Agents Chemother.61, e00642–17.

    Google Scholar 

  • Hecker, S.J., Reddy, R.K., Glinka, T., and Rodny, O. 2020a. Boronic acid derivatives and therapeutic uses thereof. US Patent 1057-0159B2, Qpex Biopharma, Inc., San Diego, USA.

    Google Scholar 

  • Hecker, S.J., Reddy, R.K., Lomovskaya, O., Griffith, D.C., Rubio-Aparicio, D., Nelson, K., Tsivkovski, R., Sun, D., Sabet, M., Tarazi, Z., et al. 2020b. Discovery of cyclic boronic acid QPX7728, an ultrabroad-spectrum inhibitor of serine and metallo-β-lactamases. J. Med. Chem. DOI: https://doi.org/10.1021/acs.jmedchem.9b01976.

    Google Scholar 

  • Heinz, U., Bauer, R., Wommer, S., Meyer-Klaucke, W., Papamichaels, C., Bateson, J., and Adolph, H.W. 2003. Coordination geometries of metal ions in D- or L-captopril-inhibited metallo-β-lactamases. J. Biol. Chem.278, 20659–20666.

    CAS  PubMed  Google Scholar 

  • Higgins, P.G., Wisplinghoff, H., Stefanik, D., and Seifert, H. 2004. In vitro activities of the β-lactamase inhibitors clavulanic acid, sulbactam, and tazobactam alone or in combination with β-lactams against epidemiologically characterized multidrug-resistant Acinetobacter baumannii strains. Antimicrob. Agent Chemother.48, 1586–1592.

    CAS  Google Scholar 

  • Hirsch, E.B., Ledesma, K.R., Chang, K.T., Schwartz, M.S., Motyl, M.R., and Tam, V.H. 2012. In vitro activity of MK-7655, a novel β-lactamase inhibitor, in combination with imipenem against carbapenem-resistant Gram-negative bacteria. Antimicrob. Agents Chemother.56, 3753–3757.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Holten, K.B. and Onusko, E.M. 2000. Appropriate prescribing of oral β-lactam antibiotics. Am. Fam. Physician.62, 611–620.

    CAS  PubMed  Google Scholar 

  • Iyer, R., Moussa, S.H., Durand-Réville, T.F., Tommasi, R., and Miller, A. 2018. Acinetobacter baumanni OmpA is a selective antibiotic permeant porin. ACS Infect. Dis.4, 373–381.

    CAS  PubMed  Google Scholar 

  • Jacoby, G.A. 2009. AmpC β-lactamases. Clin. Microbiol. Rev.22, 161–182.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jones, B.M., Huelfer, K., and Bland, C.M. 2020. Clinical and safety evaluation of continuously infused ceftolozane/tazobactam in the outpatient setting. Open Forum Infect. Dis.7, ofaa014.

    PubMed  PubMed Central  Google Scholar 

  • June, C.M., Vallier, B.C., Bonomo, R.A., Leonard, D.A., and Powers, R.A. 2014. Structural origins of oxacillinase specificity in class D β-lactamases. Antimicrob. Agents Chemother.58, 333–341.

    PubMed  PubMed Central  Google Scholar 

  • Kano, A., Koresawa, T., Matsumoto, K., Ouchi, S., and Kondo, K. 2015. First in human study to assess safety, tolerability and pharmacokinetics of β-lactamase inhibitor OP0595. Abstracts of the Twenty-fifth European Congress of Clinical Microbiology and Infectious Diseases, Copenhagen (ESCMID), Basel, Switzerland. Abs. P0236.

    Google Scholar 

  • Kim, M.K., An, Y.J., Na, J.H., Seol, J.H., Ryu, J.Y., Lee, J.W., Kang, L.W., Chung, K.M., Lee, J.H., Moon, J.H., et al. 2017. Structural and mechanistic insights into the inhibition of class C β-lactamases through the adenylylation of the nucleophilic serine. J. Antimicrob. Chemother. 72, 735–743.

    CAS  PubMed  Google Scholar 

  • Kim, J.Y., Jung, H.I., An, Y.J., Lee, J.H., Kim, S.J., Jeong, S.H., Lee, K.J., Suh, P.G., Lee, H.S., Lee, S.H., et al. 2006. Structural basis for the extended substrate spectrum of CMY-10, a plasmid-encoded class C β-lactamase. Mol. Microbiol.60, 907–916.

    CAS  PubMed  Google Scholar 

  • Krajnc, A., Brem, J., Hinchliffe, P., Calvopiña, K., Panduwawala, T.D., Lang, P., Kamps, J.J.A.G., Tyrrell, J.M., Widlake, E., Saward, B.G., et al. 2019. Bicyclic boronate VNRX-5133 inhibits metallo- and serine-β-Lactamase. J. Med. Chem.62, 8544–8556.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Krajnc, A., Lang, P.A., Panduwawala, T.D., Brem, J., and Schofield, C.J. 2019. Will morphing boron-based inhibitors beat the β-lactamases? Curr. Opin. Chem. Biol.50, 101–110.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu, B., Trout, R.E.L., Chu, G.H., McGarry, D., Jackson, R.W., Hamrick, J.C., Diagle, D.M., Cusick, S.M., Pozzi, C., de Luca, F., et al. 2020. Discovery of Taniborbactam (VNRX-5133): a broad-spectrum serine- and metallo-β-lactamase inhibitor for carbapenem-resistant bacterial infections. J. Med. Chem.63, 2789–2801.

    CAS  PubMed  Google Scholar 

  • Livermore, D.M., Mushtaq, S., Warner, M., Vickers, A., and Woodford, N. 2017. In vitro activity of Cefepime/Zidebactam (WCK 5222) against Gram-negative bacteria. J. Antimicrob. Chemother.72, 1373–1385.

    CAS  PubMed  Google Scholar 

  • Lob, S.H., Hackel, M.A., Kazmierczak, K.M., Young, K., Motyl, M.R., Karlowsky, J.A., and Sahm, D.F. 2017. In vitro activity of imipenem-relebactam against Gram-negative ESKAPE pathogens isolated by clinical laboratories in the United States in 2015 (results from the SMART global surveillance program). Antimicrob. Agents Chemother.61, e02209–16.

    PubMed  PubMed Central  Google Scholar 

  • Mammeri, H., Poirel, L., and Nordmann, P. 2007. Extension of the hydrolysis spectrum of AmpC β-lactamase of Escherichia coli due to amino acid insertion in the H-10 helix. J. Antimicrob. Chemother.60, 490–494.

    CAS  PubMed  Google Scholar 

  • McLeod, S., Carter, N., Hackel, M., Badal, R., Mueller, J., Tommasi, R., and Miller, A. 2018. The novel β-lactamase inhibitor ETX1317 effectively restores the activity of cefpodoxime against extended spectrum β-lactamase (ESBL)- and carbapenemase-expressing enterobacteriaceae isolated from recent urinary tract infections. ASM Microbe Atlanta, Georgia, USA. Friday-603.

    Google Scholar 

  • McLeod, S., Shapiro, A., Moussa, S., Carter, N., Johnstone, M., McLaughlin, R., Dejonge, B., Tommasi, R., Mueller, J., Miller, A. 2016. Sulbactam combined with the novel β-lactamase inhibitor ETX2514 for the treatment of multidrug-resistant Acinetobacter baumannii infections. Open Forum Infect. Dis.3, suppl_1.

  • Mendes, R.E., Rhomberg, P.R., Watters, A.A., Castanheira, M., and Flamm, R. 2019. In vitro activity of the orally available ceftibuten/VNRX-7145 combination against a challenge set of Enterobacteriaceae pathogens carrying molecularly characterized β-lactamase genes. European Congress of Clinical Microbiology and Infectious Diseases (29th ECCMID), Amsterdam, Netherlands. Abs. P1180.

    Google Scholar 

  • Morán-Barrio, J., Lisa, M.N., Larrieux, N., Drusin, S.I., Viale, A.M., Moreno, D.M., Buschiazzo, A., and Vila, A.J. 2016. Crystal structure of the metallo-β-lactamase GOB in the periplasmic dizinc form reveals an unusual metal site. Antimicrob. Agents Chemother. 60, 6013–6022.

    PubMed  PubMed Central  Google Scholar 

  • Morandi, S., Morandi, F., Caselli, E., Shoichet, B.K., and Prati, F. 2008. Structure-based optimization of cephalothin-analogue boronic acids as β-lactamase inhibitors. Bioorg. Med. Chem.16, 1195–1205.

    CAS  PubMed  Google Scholar 

  • Morinaka, A., Tsutsumi, Y., Yamada, M., Suzuki, K., Watanabe, T., Abe, T., Furuuchi, T., Inamura, S., Sakamaki, Y., Mitsuhashi, N., et al. 2015. OP0595, a new diazabicyclooctane: mode of action as a serine β-lactamase inhibitor, antibiotic and β-lactam ‘Enhancer’. J. Antimicrob. Chemother.70, 2779–2786.

    CAS  PubMed  Google Scholar 

  • Morrissey, I., Magnet, S., Hawser, S., Shapiro, S., and Knechtle, P. 2019. In vitro activity of cefepime-enmetazobactam against Gram-negative isolates collected from U.S. and European hospitals during 2014–2015. Antimicrob. Agents Chemother.63, e00514–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Moya, B., Barcelo, I.M., Bhagwat, S., Patel, M., Bou, G., Papp-Wallace, K.M., Bonomo, R.A., and Oliver, A. 2017a. Potent β-lactam enhancer activity of Zidebactam and WCK 5153 against Acinetobacter baumannii, including carbapenemase-producing clinical isolates. Antimicrob. Agents Chemother.61, e01238–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Moya, B., Barcelo, I.M., Bhagwat, S., Patel, M., Bou, G., Papp-Wallace, K.M., Bonomo, R.A., and Oliver, A. 2017b. WCK 5107 (Zidebactam) and WCK 5153 are novel inhibitors of PBP2 showing potent “β-lactam enhancer” activity against Pseudomonas aeruginosa, including multidrug-resistant metallo-β-lactamase-producing high-risk clones. Antimicrob. Agents Chemother.61, e02529–16.

    PubMed  PubMed Central  Google Scholar 

  • Mushtaq, S., Vickers, A., Woodford, N., and Livermore, D. 2018. Potentiation of cefepime by the boronate VNRX-5133 versus Gram-negative bacteria with known β-lactamases. European Congress of Clinical Microbiology and Infectious Diseases (28th ECCMID), Madrid Spain. Abs. P1536.

    Google Scholar 

  • Na, J.H., An, Y.J., and Cha, S.S. 2017. GMP and IMP are competitive inhibitors of CMY-10, an extended-spectrum class C β-lactamase. Antimicrob. Agents Chemother. 61, e00098–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Na, J.H. and Cha, S.S. 2016. Structural basis for the extended substrate spectrum of AmpC BER and structure-guided discovery of the inhibition activity of citrate against the class C β-lactamases AmpC BER and CMY-10. Acta Cryst. D Struct. Biol.72, 976–985.

    CAS  Google Scholar 

  • Na, J.H., Lee, T.H., Park, S.B., Kim, M.K., Jeong, B.G., Chung, K.M., and Cha, S.S. 2018. In vitro and in vivo inhibitory activity of NADPH against the AmpC BER class C β-lactamase. Front. Cell. Infect. Microbiol.8, 441.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nordmann, P. and Mammeri, H. 2007. Extended-spectrum cephalosporinases: structure, detection and epidemiology. Future Microbiol.2, 297–307.

    CAS  PubMed  Google Scholar 

  • O’Donnell, J., Chen, A., Tanudra, A., Mueller, J., Tommasi, R., Miller, A., Carter, N., McLeod, S., Comita-Prevoir, J., and Durand-Réville, T. 2017. Cefpodoxime proxetil/ETX0282: a novel oral β-lactam/β-lactamase inhibitor combination to treat the emerging threat of multi-drug resistant Enterobacteriaceae. ASM Microbe, New Orleans, Louisiana, USA.

    Google Scholar 

  • Page, M.I. and Badarau, A. 2008. The mechanisms of catalysis by metallo β-lactamases. Bioinorg. Chem. Appl.2008, 576297.

    PubMed Central  Google Scholar 

  • Papp-Wallace, K.M. 2019. The latest advances in β-lactam-β-lactamase inhibitor combinations for the treatment of Gram-negative bacterial infections. Expert Opin. Pharmacother.20, 2169–2184.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Papp-Wallace, K.M., Bethel, C.R., Barnes, M.D., Rutter, J.D., Taracila, M.A., Bajaksouzian, S., Jacobs, M.R., and Bonomo, R.A. 2017. AAI101, a novel β-lactamase inhibitor: microbiological and enzymatic profiling. Open Forum Infect. Dis.4(suppl_1), S375.

    PubMed Central  Google Scholar 

  • Papp-Wallace, K.M., Bethel, C.R., Caillon, J., Barnes, M.D., Potel, G., Bajaksouzian, S., Rutter, J.D., Reghal, A., Shapiro, S., Taracila, M.A., et al. 2019. Beyond piperacillin-tazobactam: cefepime and AAI101 as a potent β-lactam-β-lactamase inhibitor combination. Antimicrob. Agents Chemother.63, e00105–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Papp-Wallace, K.M. and Bonomo, R.A. 2016. New β-lactamase inhibitors in the clinic. Infect. Dis. Clin. North Am.30, 441–464.

    PubMed  PubMed Central  Google Scholar 

  • Papp-Wallace, K.M., Nguyen, N.Q., Jacobs, M.R., Bethel, C.R., Barnes, M.D., Kumar, V., Bajaksouzian, S., Rudin, S.D., Rather, P.N., Bhavsar, S., et al. 2018. Strategic approaches to overcome resistance against Gram-negative pathogens using β-lactamase inhibitors and β-lactam enhancers activity of three novel Diazabicyclooctanes WCK 5153, Zidebactam (WCK 5107), and WCK 4234. J. Med. Chem.61, 4067–4086.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Penwell, W.F., Shapiro, A.B., Giacobbe, R.A., Gu, R.F., Gao, N., Thresher, J., McLaughlin, R.E., Huband, M.D., DeJonge, B.L.M., Ehmann, D.E., et al. 2015. Molecular mechanisms of sulbactam antibacterial activity and resistance determinants in Acinetobacter baumannii. Antimicrob. Agents Chemother.59, 1680–1689.

    PubMed  PubMed Central  Google Scholar 

  • Perez, F., Hujer, A.M., Hujer, K.M., Decker, B.K., Rather, P.N., and Bonomo, R.A. 2007. Global challenge of multidrug-resistant Acinetobacter baumannii. Antimicrob. Agents Chemother.51, 3471–3484.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Petty, L.A., Henig, O., Patel, T.S., Pogue, J.M., and Kaye, K.S. 2018. Overview of meropenem-vaborbactam and newer antimicrobial agents for the treatment of carbapenem-resistant Enterobacteriaceae. Infect. Drug Resist.11, 1461–1472.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Philippon, A., Arlet, G., and Jacoby, G.A. 2002. Plasmid-determined AmpC-type β-lactamases. Antimicrob. Agents Chemother.46, 1–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Philippon, A., Labia, R., and Jacoby, G. 1989. Extended-spectrum β-lactamases. Antimicrob. Agents Chemother.33, 1131–1136.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pogue, J.M., Kaye, K.S., Cohen, D.A., and Marchaim, D. 2015. Appropriate antimicrobial therapy in the era of multidrug-resistant human pathogens. Clin. Microbiol. Infect.21, 302–312.

    CAS  PubMed  Google Scholar 

  • Pratt, R.F. 2008. Substrate specificity of bacterial DD-peptidases (penicillin-binding proteins). Cell. Mol. Life Sci.65, 2138–2155.

    CAS  PubMed  Google Scholar 

  • Qin, W., Panunzio, M., and Biondi, S. 2014. β-Lactam antibiotics renaissance. Antibiotics3, 193–215.

    PubMed  PubMed Central  Google Scholar 

  • Queenan, A.M. and Bush, K. 2007. Carbapenemases: the versatile β-lactamases. Clin. Microbiol. Rev.20, 440–458.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rawat, D. and Nair, D. 2010. Extended-spectrum β-lactamases in Gram negative bacteria. J. Glob. Infect. Dis.2, 263–274.

    PubMed  PubMed Central  Google Scholar 

  • Rice, L.B. 2008. Federal funding for the study of antimicrobial resistance in nosocomial pathogens: No ESKAPE. J. Infect. Dis.197, 1079–1081.

    PubMed  Google Scholar 

  • Sader, H.S., Flamm, R.K., Huband, M.D., Rhomberg, P.R., and Castanheira, M. 2017. Antimicrobial activity of meropenem-WCK 4234 (WCK 5999) against clinical isolates of Acinetobacter spp. collected worldwide and stratified by infection type. ASM Microbe, New Orleans, Louisiana, USA.

    Google Scholar 

  • Sader, H.S., Mendes, R.E., Pfaller, M.A., Shortridge, D., Flamm, R.K., and Castanheira, M. 2018. Antimicrobial activities of aztreonam-avibactam and comparator agents against contemporary (2016) clinical Enterobacteriaceae isolates. Antimicrob. Agents Chemother.62, e01856–17.

    PubMed  Google Scholar 

  • Santajit, S. and Indrawattana, N. 2016. Mechanisms of antimicrobial resistance in ESKAPE pathogens. Biomed Res. Int.2016, 2475067.

    PubMed  PubMed Central  Google Scholar 

  • Santillana, E., Beceiro, A., Bou, G., and Romero, A. 2007. Crystal structure of the carbapenemase OXA-24 reveals insights into the mechanism of carbapenem hydrolysis. Proc. Natl. Acad. Sci. USA104, 5354–5359.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Schultsz, C. and Geerlings, S. 2012. Plasmid-mediated resistance in Enterobacteriaceae: changing landscape and implications for therapy. Drugs72, 1–16.

    CAS  PubMed  Google Scholar 

  • Schwarz, S., Loeffler, A., and Kadlec, K. 2017. Bacterial resistance to antimicrobial agents and its impact on veterinary and human medicine. Vet. Dermatol.28, 82–e19.

    PubMed  Google Scholar 

  • Shrivastava, S.M., Kumar, S., and Chaudhary, M. 2009. Ceftriaxone-sulbactam combination: microbial analysis by variation of ratios and comparative disc diffusion. Curr. Res. Bacteriol.2, 50–55.

    Google Scholar 

  • Smet, A., Martel, A., Persoons, D., Dewulf, J., Heyndrickx, M., Herman, L., Haesebrouck, F., and Butaye, P. 2010. Broad-spectrum β-lactamases among Enterobacteriaceae of animal origin: molecular aspects, mobility and impact on public health. FEMS Microbiol. Rev.34, 295–316.

    CAS  PubMed  Google Scholar 

  • Spicer, T., Minond, D., Enogieru, I., Saldanha, S.A., Allais, C., Liu, Q., Mercer, B.A., Roush, W.R., and Hodder, P. 2014. ML302, a novel β-lactamase (BLA) inhibitor. In Probe Reports from the NIH Molecular Libraries Program [Internet]. National Center for Biotechnology Information (US).

    Google Scholar 

  • Stachyra, T., Péchereau, M.C., Bruneau, J.M., Claudon, M., Frere, J.M., Miossec, C., Coleman, K., and Black, M.T. 2010. Mechanistic studies of the inactivation of TEM-1 and P99 by NXL104, a novel non-β-lactam β-lactamase inhibitor. Antimicrob. Agents Chemother. 54, 5132–5138.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Takeda, S., Ishii, Y., Hatano, K., Tateda, K., and Yamaguchi, K. 2007. Stability of FR264205 against AmpC β-lactamase of Pseudomonas aeruginosa. Int. J. Antimicrob. Agents.30, 443–445.

    CAS  PubMed  Google Scholar 

  • Tehrani, K.H.M.E. and Martin, N.I. 2018. β-lactam/β-lactamase inhibitor combinations: an update. Medchemcomm.9, 1439–1456.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Testa, R., Cantón, R., Giani, T., Morosini, M.I., Nichols, W.W., Seifert, H., Stefanik, D., Rossolini, G.M., and Nordmann, P. 2015. In vitro activity of ceftazidime, ceftaroline and aztreonam alone and in combination with avibactam against european Gram-negative and Gram-positive clinical isolates. Int. J. Antimicrob. Agents.45, 641–646.

    CAS  PubMed  Google Scholar 

  • Therrien, C. and Levesque, R.C. 2000. Molecular basis of antibiotic resistance and β-lactamase inhibition by mechanism-based inactivators: perspectives and future directions. FEMS Microbiol. Rev.24, 251–262.

    CAS  PubMed  Google Scholar 

  • Theuretzbacher, U., Bush, K., Harbarth, S., Paul, M., Rex, J.H., Tacconelli, E., and Thwaites, G.E. 2020. Critical analysis of antibacterial agents in clinical development. Nat. Rev. Microbiol.18, 286–298.

    CAS  PubMed  Google Scholar 

  • Toney, J.H., Hammond, G.G., Fitzgerald, P.M., Sharma, N., Balkovec, J.M., Rouen, G.P., Olson, S.H., Hammond, M.L., Greenlee M.L., and Gao, Y.D. 2001. Succinic acids as potent inhibitors of plasmid-borne IMP-1 metallo-β-lactamase. J. Biol. Chem.276, 31913–31918.

    CAS  PubMed  Google Scholar 

  • Tsivkovski, R., Totrov, M., Lomovskaya, O. 2020. Biochemical characterization of QP7728, a new ultrabroad-spectrum β-lactamase inhibitor of serine and metallo-β-lactamases. Antimicrob. Agents Chemother.64, e00130–20.

    PubMed  PubMed Central  Google Scholar 

  • Tyers, M. and Wright, G.D. 2019. Drug combinations: a strategy to extend the life of antibiotics in the 21st century. Nat. Rev. Microbiol.17, 141–155.

    CAS  PubMed  Google Scholar 

  • Typas, A., Banzhaf, M., Gross, C.A., and Vollmer, W. 2011. From the regulation of peptidoglycan synthesis to bacterial growth and morphology. Nat. Rev. Microbiol.10, 123–136.

    PubMed  PubMed Central  Google Scholar 

  • Wang, D.Y., Abboud, M.I., Markoulides, M.S., Brem, J., and Schofield, C.J. 2016. The road to avibactam: the first clinically useful non-β-lactam working somewhat like a β-lactam. Future Med. Chem.8, 1063–1084.

    CAS  PubMed  Google Scholar 

  • Wang, Y., Wang, J., Wang, R., and Cai, Y. 2020. Resistance to ceftazidime-avibactam and underlying mechanisms. J. Glob. Antimicrob. Resist.22, 18–27.

    PubMed  Google Scholar 

  • Yusof, Y., Tan, D.T.C., Arjomandi, O.K., Schenk, G., and McGeary, R.P. 2016. Captopril analogues as metallo-β-lactamase inhibitors. Bioorg. Med. Chem. Lett.26, 1589–1593.

    CAS  PubMed  Google Scholar 

  • Zervosen, A., Sauvage, E., Frère, J.M., Charlier, P., and Luxen, A. 2012. Development of new drugs for an old target-the penicillin binding proteins. Molecules17, 12478–12505.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhanel, G.G., Lawson, C.D., Adam, H., Schweizer, F., Zelenitsky, S., Lagacé-Wiens, R.S., Denisuik, A., Gin, A.S., Hoban, D.J., Lynch, J.P., et al. 2013. Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Drugs73, 159–177.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by Jungwon University Research Grant (2017-022).

Author information

Authors and Affiliations

  1. Department of Medicinal Chemistry, Jungwon University, Goesan, 28420, Republic of Korea

    Shivakumar S. Jalde & Hyun Kyung Choi

Authors
  1. Shivakumar S. Jalde
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hyun Kyung Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hyun Kyung Choi.

Ethics declarations

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jalde, S.S., Choi, H.K. Recent advances in the development of β-lactamase inhibitors. J Microbiol. 58, 633–647 (2020). https://doi.org/10.1007/s12275-020-0285-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12275-020-0285-z

Keywords

Search

Navigation