New β-lactamase Inhibitors: a Therapeutic Renaissance in an MDR World

Overview

Journal Antimicrob Agents Chemother

Publisher American Society for Microbiology

Specialty Pharmacology

Date 2014 Jan 1

PMID 24379206

Citations 115

Authors

Sarah M Drawz

Krisztina M Papp-Wallace

Robert A Bonomo

Affiliations

Soon will be listed here.

Abstract

As the incidence of Gram-negative bacterial infections for which few effective treatments remain increases, so does the contribution of drug-hydrolyzing β-lactamase enzymes to this serious clinical problem. This review highlights recent advances in β-lactamase inhibitors and focuses on agents with novel mechanisms of action against a wide range of enzymes. To this end, we review the β-lactamase inhibitors currently in clinical trials, select agents still in preclinical development, and older therapeutic approaches that are being revisited. Particular emphasis is placed on the activity of compounds at the forefront of the developmental pipeline, including the diazabicyclooctane inhibitors (avibactam and MK-7655) and the boronate RPX7009. With its novel reversible mechanism, avibactam stands to be the first new β-lactamase inhibitor brought into clinical use in the past 2 decades. Our discussion includes the importance of selecting the appropriate partner β-lactam and dosing regimens for these promising agents. This "renaissance" of β-lactamase inhibitors offers new hope in a world plagued by multidrug-resistant (MDR) Gram-negative bacteria.

Citing Articles

Pharmacokinetic/pharma-codynamic study of pralurbactam (FL058) combined with meropenem in a neutropenic murine thigh infection model.

Huang Z, Li W, Zhang R, Li Y, Li X, Bian X Front Microbiol. 2025; 15:1516979.

PMID: 39741587 PMC: 11685127. DOI: 10.3389/fmicb.2024.1516979.

Aztreonam-avibactam: The dynamic duo against multidrug-resistant gram-negative pathogens.

Al Musawa M, Bleick C, Herbin S, Caniff K, Van Helden S, Rybak M Pharmacotherapy. 2024; 44(12):927-938.

PMID: 39601336 PMC: 11687205. DOI: 10.1002/phar.4629.

Metabolic changes associated with polysaccharide utilization reduce susceptibility to some β-lactams in .

Nilson R, Penumutchu S, Pagano F, Belenky P mSphere. 2024; 9(8):e0010324.

PMID: 39109911 PMC: 11351048. DOI: 10.1128/msphere.00103-24.

Aubl. Essential Oil: Chemical Composition, In Vitro Antioxidant Activity, and Inhibitory Effects of Acetylcholinesterase, α-Glucosidase and β-Lactamase.

Zhu X, Zhu J, Xu Z, Liu X Molecules. 2024; 29(12).

PMID: 38930934 PMC: 11206966. DOI: 10.3390/molecules29122869.

Effect of ceftazidime-avibactam combined with different antimicrobials against carbapenem-resistant .

Wu Y, Yu W, Chu X, Zhang J, Jia P, Liu X Microbiol Spectr. 2024; 12(6):e0010724.

PMID: 38712934 PMC: 11237391. DOI: 10.1128/spectrum.00107-24.

References

King D, Worrall L, Gruninger R, Strynadka N . New Delhi metallo-β-lactamase: structural insights into β-lactam recognition and inhibition. J Am Chem Soc. 2012; 134(28):11362-5. DOI: 10.1021/ja303579d. View

Nordmann P, Poirel L, Walsh T, Livermore D . The emerging NDM carbapenemases. Trends Microbiol. 2011; 19(12):588-95. DOI: 10.1016/j.tim.2011.09.005. View

Drawz S, Babic M, Bethel C, Taracila M, Distler A, Ori C . Inhibition of the class C beta-lactamase from Acinetobacter spp.: insights into effective inhibitor design. Biochemistry. 2009; 49(2):329-40. PMC: 2810401. DOI: 10.1021/bi9015988. View

Mohamed M, Hussein W, McGeary R, Vella P, Schenk G, El-Hameed R . Synthesis and kinetic testing of new inhibitors for a metallo-β-lactamase from Klebsiella pneumonia and Pseudomonas aeruginosa. Eur J Med Chem. 2011; 46(12):6075-82. DOI: 10.1016/j.ejmech.2011.10.030. View

. White paper: recommendations on the conduct of superiority and organism-specific clinical trials of antibacterial agents for the treatment of infections caused by drug-resistant bacterial pathogens. Clin Infect Dis. 2012; 55(8):1031-46. PMC: 3657525. DOI: 10.1093/cid/cis688. View

Vaara M . Agents that increase the permeability of the outer membrane. Microbiol Rev. 1992; 56(3):395-411. PMC: 372877. DOI: 10.1128/mr.56.3.395-411.1992. View

Poirel L, Naas T, Nordmann P . Diversity, epidemiology, and genetics of class D beta-lactamases. Antimicrob Agents Chemother. 2009; 54(1):24-38. PMC: 2798486. DOI: 10.1128/AAC.01512-08. View

Bou G, Santillana E, Sheri A, Beceiro A, Sampson J, Kalp M . Design, synthesis, and crystal structures of 6-alkylidene-2'-substituted penicillanic acid sulfones as potent inhibitors of Acinetobacter baumannii OXA-24 carbapenemase. J Am Chem Soc. 2010; 132(38):13320-31. PMC: 3393087. DOI: 10.1021/ja104092z. View

Ke W, Bethel C, Papp-Wallace K, Pagadala S, Nottingham M, Fernandez D . Crystal structures of KPC-2 β-lactamase in complex with 3-nitrophenyl boronic acid and the penam sulfone PSR-3-226. Antimicrob Agents Chemother. 2012; 56(5):2713-8. PMC: 3346646. DOI: 10.1128/AAC.06099-11. View

10.

Castanheira M, Sader H, Farrell D, Mendes R, Jones R . Activity of ceftaroline-avibactam tested against Gram-negative organism populations, including strains expressing one or more β-lactamases and methicillin-resistant Staphylococcus aureus carrying various staphylococcal cassette chromosome mec types. Antimicrob Agents Chemother. 2012; 56(9):4779-85. PMC: 3421892. DOI: 10.1128/AAC.00817-12. View

11.

Boucher H, Talbot G, Benjamin Jr D, Bradley J, Guidos R, Jones R . 10 x '20 Progress--development of new drugs active against gram-negative bacilli: an update from the Infectious Diseases Society of America. Clin Infect Dis. 2013; 56(12):1685-94. PMC: 3707426. DOI: 10.1093/cid/cit152. View

12.

Poeylaut-Palena A, Tomatis P, Karsisiotis A, Damblon C, Mata E, Vila A . A minimalistic approach to identify substrate binding features in B1 Metallo-beta-lactamases. Bioorg Med Chem Lett. 2007; 17(18):5171-4. DOI: 10.1016/j.bmcl.2007.06.089. View

13.

Fluckiger U, Segessenmann C, Gerber A . Integration of pharmacokinetics and pharmacodynamics of imipenem in a human-adapted mouse model. Antimicrob Agents Chemother. 1991; 35(9):1905-10. PMC: 245289. DOI: 10.1128/AAC.35.9.1905. View

14.

Patel G, Bonomo R . "Stormy waters ahead": global emergence of carbapenemases. Front Microbiol. 2013; 4:48. PMC: 3596785. DOI: 10.3389/fmicb.2013.00048. View

15.

Crandon J, Schuck V, Banevicius M, Beaudoin M, Nichols W, Tanudra M . Comparative in vitro and in vivo efficacies of human simulated doses of ceftazidime and ceftazidime-avibactam against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2012; 56(12):6137-46. PMC: 3497209. DOI: 10.1128/AAC.00851-12. View

16.

Widmann M, Pleiss J, Oelschlaeger P . Systematic analysis of metallo-β-lactamases using an automated database. Antimicrob Agents Chemother. 2012; 56(7):3481-91. PMC: 3393435. DOI: 10.1128/AAC.00255-12. View

17.

Tan Q, Ogawa A, Raghoobar S, Wisniewski D, Colwell L, Park Y . Thiophenyl oxime-derived phosphonates as nano-molar class C beta-lactamase inhibitors reducing MIC of imipenem against Pseudomonas aeruginosa and Acinetobacter baumannii. Bioorg Med Chem Lett. 2011; 21(14):4363-5. DOI: 10.1016/j.bmcl.2011.04.122. View

18.

Lee K, Lim Y, Yong D, Yum J, Chong Y . Evaluation of the Hodge test and the imipenem-EDTA double-disk synergy test for differentiating metallo-beta-lactamase-producing isolates of Pseudomonas spp. and Acinetobacter spp. J Clin Microbiol. 2003; 41(10):4623-9. PMC: 254300. DOI: 10.1128/JCM.41.10.4623-4629.2003. View

19.

Morandi F, Caselli E, Morandi S, Focia P, Blazquez J, Shoichet B . Nanomolar inhibitors of AmpC beta-lactamase. J Am Chem Soc. 2003; 125(3):685-95. DOI: 10.1021/ja0288338. View

20.

Lahiri S, Mangani S, Durand-Reville T, Benvenuti M, De Luca F, Sanyal G . Structural insight into potent broad-spectrum inhibition with reversible recyclization mechanism: avibactam in complex with CTX-M-15 and Pseudomonas aeruginosa AmpC β-lactamases. Antimicrob Agents Chemother. 2013; 57(6):2496-505. PMC: 3716117. DOI: 10.1128/AAC.02247-12. View