β-Lactamase inhibitor

Beta lactamases are a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. They act by breaking the beta-lactam ring that allows penicillin-like antibiotics to work. Strategies for combatting this form of resistance have included the development of new beta lactam antibiotics that are more resistant to cleavage, and the development of beta lactamase inhibitors.[1] Although β-lactamase inhibitors have little antibiotic activity of their own,[2] they prevent bacterial degradation of beta lactam antibiotics and thus extend the range of bacteria the drugs 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-(-) bacteria, as beta lactamase production is an important contributor to beta lactam resistance in these pathogens. In contrast, most beta lactam resistance in Gram-(+) bacteria is due variations in penicillin-binding proteins that lead to reduced binding to the beta lactam.[3][4] The Gram-(+) 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

The Ambler classification system groups known beta lactamase enzymes into four groups according to sequence homology and presumed phylogenetic relationships. Classes A, C and D cleave beta lactams by a multi-step mechanism analogous to the mechanism of serine proteases. Upon binding, a serine hydroxyl group in the beta lactamase active site forms a transient covalent bond to the beta lactam ring carbonyl group, cleaving the beta lactam ring in the process. In a second step, nucleophilic attack by a water molecule cleaves the covalent bond between the enzyme and the carbonyl group of the erstwhile beta lactam. This allows the degraded beta lactam to diffuse away and frees up the enzyme to process additional beta lactam molecules.

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 formed covalent intermediate is very stable. The persistence of the covalent bond between the beta lactamase inhibitor and the beta lactamase binding site deactivates the enzyme and prevents processing of beta lactam antibiotics.[7]

Ambler Class B beta lactams 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.[8]

Commonly used agents

Currently marketed β-lactamase inhibitors are not sold as individual drugs. Instead they are co-formulated with a β-lactam that has 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-(−) 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.[10]

Beta-lactamase producing bacteria

Bacteria that can produce beta-lactamases include, but are not limited to:

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.[12] 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 convinient 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 clavulonic 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 have to potential to be tailored to the many different isoforms of beta-lactamses, and therefore have the potential to reestablish potency of beta-lactam antibiotics.[13]

References

  1. ↑ Essack SY (2001). "The development of beta-lactam antibiotics in response to the evolution of beta-lactamases". Pharm. Res. 18 (10): 1391–9. PMID 11697463.
  2. ↑ "Beta-Lactamase Inhibitors". Department of Nursing of the Fort Hays State University College of Health and Life Sciences. October 2000. Archived from the original on 2007-09-27. Retrieved 2007-08-17.
  3. ↑ Georgopapadakou NH (1993). "Penicillin-binding proteins and bacterial resistance to beta-lactams". Antimicrob. Agents Chemother. 37 (10): 2045–53. doi:10.1128/aac.37.10.2045. PMC 192226. PMID 8257121.
  4. ↑ Zapun A, Contreras-Martel C, Vernet T (2008). "Penicillin-binding proteins and beta-lactam resistance". FEMS Microbiol. Rev. 32 (2): 361–85. doi:10.1111/j.1574-6976.2007.00095.x. PMID 18248419.
  5. ↑ Curello J, MacDougall C (2014). "Beyond Susceptible and Resistant, Part II: Treatment of Infections Due to Gram-Negative Organisms Producing Extended-Spectrum β-Lactamases". J Pediatr Pharmacol Ther 19 (3): 156–64. doi:10.5863/1551-6776-19.3.156. PMC 4187532. PMID 25309145.
  6. ↑ Wolter DJ, Lister PD (2013). "Mechanisms of β-lactam resistance among Pseudomonas aeruginosa". Curr. Pharm. Des. 19 (2): 209–22. doi:10.2174/13816128130203. PMID 22894618.
  7. ↑ Drawz SM, Bonomo RA (2010). "Three decades of beta-lactamase inhibitors". Clin. Microbiol. Rev. 23 (1): 160–201. doi:10.1128/CMR.00037-09. PMC 2806661. PMID 20065329.
  8. ↑ Biedenbach D, Bouchillon S, Hackel M, Hoban D, Kazmierczak K, Hawser S, Badal R (2015). "Dissemination of NDM metallo-β-lactamase genes among clinical isolates of Enterobacteriaceae collected during the SMART global surveillance study from 2008 to 2012". Antimicrob. Agents Chemother. 59 (2): 826–30. doi:10.1128/AAC.03938-14. PMC 4335866. PMID 25403666.
  9. ↑ Drawz SM, Bonomo RA (2010). "Three decades of beta-lactamase inhibitors". Clin. Microbiol. Rev. 23 (1): 160–201. doi:10.1128/CMR.00037-09. PMC 2806661. PMID 20065329.
  10. ↑ Watson ID, Stewart MJ, Platt DJ (1988). "Clinical pharmacokinetics of enzyme inhibitors in antimicrobial chemotherapy". Clin Pharmacokinet 15 (3): 133–64. doi:10.2165/00003088-198815030-00001. PMID 3052984.
  11. ↑ "Cilastatin/imipenem/relebactam — AdisInsight". Springer International Publishing AG. Retrieved 29 April 2016.
  12. ↑ Livermore, David M. (October 1995). "β-Lactamases in Laboratory and Clinical Resistance". Clinical Microbiology Reviews 8 (4): 557–84. PMC 172876. PMID 8665470.
  13. ↑ Leonard, David A.; Bonomo, Robert A.; Powers, Rachel (2012). "Class D β‑Lactamases: A Reappraisal after Five Decades". Accounts of Chemical Research.

External links

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