Biology:β-Lactamase inhibitor

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Short description: Drugs that inhibit β-Lactamase enzymes

Clavulanic acid
Sulbactam
Tazobactam
Avibactam
Durlobactam
Relebactam
Vaborbactam
File:Enmetazobactam.svg
Enmetazobactam

A β-Lactamase inhibitor is a chemical compound that prevents bacterial degradation of β-lactam (beta-lactam) antibiotics.

Beta-lactamases are a family of enzymes which create bacterial resistance to beta-lactam antibiotics by degrading the drugs' beta-lactam rings, rendering them ineffective.

Strategies for combating this have included the development of both more cleavage-resistant beta-lactam antibiotics and the class of beta-lactamase specific enzyme inhibitors.[1] Although these inhibitors have little antibiotic activity of their own,[2] they are successful in extending the range of bacteria that beta-lactam antibiotics are effective against.

Medical uses

The most important use of beta-lactamase inhibitors is in the treatment of infections known or believed to be caused by gram-negative bacteria, as beta-lactamase production is an important contributor to beta-lactam resistance in these pathogens. In contrast, most beta-lactam resistance in gram-positive bacteria is due to variations in penicillin-binding proteins that lead to reduced binding to the beta-lactam.[3][4] The gram-positive pathogen Staphylococcus aureus produces beta-lactamases, but beta-lactamase inhibitors play a lesser role in treatment of these infections because the most resistant strains (methicillin-resistant Staphylococcus aureus) also use variant penicillin-binding proteins.[5][6]

Mechanism of action

Currently available beta-lactamase inhibitors are effective against Ambler Class A beta-lactamases (tazobactam, clavulanate, and sulbactam) or against Ambler Class A, C and some Class D beta-lactamases (avibactam). Like beta-lactam antibiotics, they are processed by beta-lactamases to form an initial covalent intermediate. Unlike the case of beta-lactam antibiotics, the inhibitors act as suicide substrates (tazobactam and sulbactam) which ultimately leads to the degradation of the beta-lactamase.[7] Avibactam on the other hand does not contain a beta-lactam ring (non beta-lactam beta-lactamase inhibitor), and instead binds reversibly.[8][9]

Ambler Class B beta-lactamases cleave beta-lactams by a mechanism similar to that of metalloproteases. As no covalent intermediate is formed, the mechanism of action of marketed beta-lactamase inhibitors is not applicable. Thus the spread of bacterial strains expressing metallo beta-lactamases such as the New Delhi metallo-beta-lactamase 1 has engendered considerable concern.[10]

Commonly used agents

Generally β-lactamase inhibitors are not available as individual drugs, with sulbactam being an exception, but only available in certain countries. Instead they are co-formulated with a β-lactam antibiotic with a similar serum half-life. This is done not only for dosing convenience, but also to minimize resistance development that might occur as a result of varying exposure to one or the other drug. The main classes of β-lactam antibiotics used to treat gram-negative bacterial infections include (in approximate order of intrinsic resistance to cleavage by β-lactamases) penicillins (especially aminopenicillins and ureidopenicillins), 3rd generation cephalosporins, and carbapenems. Individual β-lactamase variants may target one or many of these drug classes, and only a subset will be inhibited by a given β-lactamase inhibitor.[9] β-lactamase inhibitors expand the useful spectrum of these β-lactam antibiotics by inhibiting the β-lactamase enzymes produced by bacteria to deactivate them.[11]

  • β-lactamase inhibitors with a β-lactam core:
  • β-lactamase inhibitors with a diazabicyclooctane core:
    • Avibactam, approved in combination with ceftazidime (Avycaz, Zavicefta) and aztreonam (Emblaveo), currently undergoing clinical trials for combination with ceftaroline
    • Durlobactam, approved in combination with sulbactam (Xacduro) to treat hospital‑acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) pneumonia caused by Acinetobacter baumannii-calcoaceticus complex
    • Relebactam, used in combination with imipenem/cilastatin (Recarbrio).[12][13]
  • β-lactamase inhibitors with other types of non β-lactam cores:
    • Taniborbactam, used in combination with cefepime (cefepime/taniborbactam).[14] Has a boronic acid core.[15]
    • Vaborbactam, used in combination with meropenem (Vabomere). Has a boronic acid core.[16]
    • Xeruborbactam, the first nanomolar β-lactamase inhibitor in clinical development, has very broad-spectrum efficacy against all Ambler classes (A–D), including OXA carbapenemases and metallo-enzymes. It is a boronic acid-based transition-state analogue that strongly inhibits carbapenemases with a Ki(app) of 4 nM, which is more effective than current inhibitors. Structural investigations showed that the cyclopropyl group covalently binds to Ser70 and stabilizes the molecule by being hydrophobic. This makes borylation occur frequently and deborylation occur very rarely. Comparing it to its 2R,3S-isomer demonstrated the importance of stereochemistry in determining binding affinity and conformational stability. Molecular dynamics verified enhanced stabilization by xeruborbactam, highlighting its potential in addressing antibiotic resistance and informing the development of next-generation β-lactamase inhibitors.[17]

Beta-lactamase producing bacteria

Research

Some bacteria can produce extended spectrum β-lactamases (ESBLs) making the infection more difficult to treat and conferring additional resistance to penicillins, cephalosporins, and monobactams.[18] Boronic acid derivatives are currently under vast and extensive research as novel active site inhibitors for beta-lactamases because they contain a site that mimics the transition state that beta-lactams go through when undergoing hydrolysis via beta-lactamases. They have been found generally to fit well into the active site of many beta-lactamases and have the convenient property of being unable to be hydrolysed, and therefore rendered useless. This is a favorable drug design over many clinically used competing agents, because most of them, such as clavulanic acid, become hydrolysed, and are therefore only useful for a finite period of time. This generally causes the need for a higher concentration of competitive inhibitor than would be necessary in an unhydrolyzable inhibitor. Different boronic acid derivatives, such as taniborbactam, have the potential to be tailored to the many different isoforms of beta-lactamases, and therefore have the potential to reestablish potency of beta-lactam antibiotics.[19]

Resistance towards β-lactam/β-lactamase inhibitor combinations

There have been various reports of resistance to β-lactam/β-lactamase inhibitor combinations since their introduction into clinical practice.[20] Multiple resistance mechanisms can be observed. A common resistance mechanism is an overproduction of β-lactamases, which allows bacteria to tolerate higher concentrations of the inhibitors. Additionally, mutations in β-lactamase enzymes have been identified, that make the β-lactamase less sensitive to inhibition and compromises the efficacy of combination therapies. Other mechanisms involve modifications to the bacterial cell that affect drug entry, such as porin deficiencies.[21][22]

References

  1. ↑ "The development of beta-lactam antibiotics in response to the evolution of beta-lactamases". Pharmaceutical Research 18 (10): 1391–9. October 2001. doi:10.1023/a:1012272403776. PMID 11697463. 
  2. ↑ "Beta-Lactamase Inhibitors". Department of Nursing of the Fort Hays State University College of Health and Life Sciences. October 2000. http://www.fhsu.edu/nursing/otitis/bl_inhibit.html. 
  3. ↑ "Penicillin-binding proteins and bacterial resistance to beta-lactams". Antimicrobial Agents and Chemotherapy 37 (10): 2045–53. October 1993. doi:10.1128/aac.37.10.2045. PMID 8257121. 
  4. ↑ "Penicillin-binding proteins and beta-lactam resistance". FEMS Microbiology Reviews 32 (2): 361–85. March 2008. doi:10.1111/j.1574-6976.2007.00095.x. PMID 18248419. 
  5. ↑ "Beyond Susceptible and Resistant, Part II: Treatment of Infections Due to Gram-Negative Organisms Producing Extended-Spectrum β-Lactamases". The Journal of Pediatric Pharmacology and Therapeutics 19 (3): 156–64. July 2014. doi:10.5863/1551-6776-19.3.156. PMID 25309145. 
  6. ↑ "Mechanisms of β-lactam resistance among Pseudomonas aeruginosa". Current Pharmaceutical Design 19 (2): 209–22. 2013. doi:10.2174/13816128130203. PMID 22894618. 
  7. ↑ Patrick, Graham L. (2017). An introduction to medicinal chemistry (6th ed.). Oxford, United Kingdom. ISBN 9780198749691. OCLC 987051883. 
  8. ↑ "Structural insight into potent broad-spectrum inhibition with reversible recyclization mechanism: avibactam in complex with CTX-M-15 and Pseudomonas aeruginosa AmpC β-lactamases". Antimicrobial Agents and Chemotherapy 57 (6): 2496–505. June 2013. doi:10.1128/AAC.02247-12. PMID 23439634. 
  9. ↑ 9.0 9.1 "Three decades of beta-lactamase inhibitors". Clinical Microbiology Reviews 23 (1): 160–201. January 2010. doi:10.1128/CMR.00037-09. PMID 20065329. 
  10. ↑ "Dissemination of NDM metallo-β-lactamase genes among clinical isolates of Enterobacteriaceae collected during the SMART global surveillance study from 2008 to 2012". Antimicrobial Agents and Chemotherapy 59 (2): 826–30. February 2015. doi:10.1128/AAC.03938-14. PMID 25403666. 
  11. ↑ "Clinical pharmacokinetics of enzyme inhibitors in antimicrobial chemotherapy". Clinical Pharmacokinetics 15 (3): 133–64. September 1988. doi:10.2165/00003088-198815030-00001. PMID 3052984. 
  12. ↑ "FDA approves new treatment for complicated urinary tract and complicated intra-abdominal infections". Food and Drug Administration. July 17, 2019. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-complicated-urinary-tract-and-complicated-intra-abdominal-infections. 
  13. ↑ "Cilastatin/imipenem/relebactam — AdisInsight". Springer International Publishing AG. http://adisinsight.springer.com/drugs/800042881. 
  14. ↑ Wagenlehner, Florian (February 14, 2024). "Cefepime–Taniborbactam in Complicated Urinary Tract Infection". The New England Journal of Medicine (Massachusetts Medical Society) 390 (7): 611–622. doi:10.1056/NEJMoa2304748. PMID 38354140. https://www.nejm.org/doi/full/10.1056/NEJMoa2304748. Retrieved March 17, 2025. 
  15. ↑ Lence, Emilio (August 4, 2021). "Molecular Basis of Bicyclic Boronate β-Lactamase Inhibitors of Ultrabroad Efficacy – Insights From Molecular Dynamics Simulation Studies". frontiers in Microbiology 12 (7): 511–517. doi:10.3389/fmicb.2021.721826. PMID 8371488. 
  16. ↑ "FDA approves new antibacterial drug" (Press release). Food and Drug Administration. August 29, 2017. Archived from the original on April 23, 2019. Retrieved July 18, 2019.
  17. ↑ "Structural Insights into the Role of the Stereochemistry of the Cyclopropyl Ring in the Inhibitory Activity of Xeruborbactam against SME-1 Class A Carbapenemase". Biochemistry 64 (19): 4217–4231. September 26, 2025. doi:10.1021/acs.biochem.5c00336. PMID 41002159. 
  18. ↑ "beta-Lactamases in laboratory and clinical resistance". Clinical Microbiology Reviews 8 (4): 557–84. October 1995. doi:10.1128/cmr.8.4.557. PMID 8665470. 
  19. ↑ "Class D β-lactamases: a reappraisal after five decades". Accounts of Chemical Research 46 (11): 2407–15. November 2013. doi:10.1021/ar300327a. PMID 23902256. 
  20. ↑ Bush, Karen; Bradford, Patricia A. (May 2019). "Interplay between β-lactamases and new β-lactamase inhibitors". Nature Reviews Microbiology 17 (5): 295–306. doi:10.1038/s41579-019-0159-8. PMID 30837684. 
  21. ↑ Papp-Wallace, Krisztina M.; Mack, Andrew R.; Taracila, Magdalena A.; Bonomo, Robert A. (December 2020). "Resistance to Novel β-Lactam–β-Lactamase Inhibitor Combinations". Infectious Disease Clinics of North America 34 (4): 773–819. doi:10.1016/j.idc.2020.05.001. PMID 33011051. 
  22. ↑ Bush, Karen; Bradford, Patricia A. (May 2019). "Interplay between β-lactamases and new β-lactamase inhibitors". Nature Reviews Microbiology 17 (5): 295–306. doi:10.1038/s41579-019-0159-8. PMID 30837684. 



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