• Penicillins and others

  • Introduction: Beta-Lactamase Inhibitors: Sulbactam, Tazobactam, Avibactam, Relebactam, Clavulanic Acid.

  • • Beta-Lactam Antibiotics and Mechanism of Beta-Lactamase Inhibitors

      Attribution ClinCalc B-Lactam Antibiotics - Top 250 Drugs https://www.youtube.com/watch?v=etwNWPH0ODQ (March 1, 2015)

     

    • Sulbactam

    •  

      Tazobactam

    •  

      Avibactam

    •  

      Relebactam

    •  

      Clavulanic Acid

    • Beta-lactamase inhibitors (BLIs) are a class of drugs co-administered with beta-lactam antibiotics to combat bacterial resistance.

      • The first generation of clinically successful beta-lactamase inhibitors are beta-Lactam -containing molecules.¹

        • The Beta-lactamase inhibitor, because of its structural similarity to penicillin, binds to a serine residue at the active site of a class A or D beta-lactamase.

          • The enzyme acts on the inhibitor as it would a normal substrate, leading to the formation of the covalent acyl-enzyme intermediate.

            • Because of the formation of this intermediate, the substrate is sometimes referred to as the hemi-substrate.

            • The acyl enzyme is unstable and undergoes internal chemical rearrangements resulting in a new, highly reactive species that forms a second, and very stable covalent bond with another residue in the active site.

            • This process involves cross-linking of structures at the active center and permanently inactivates the inhibitor.¹¹ 

              • This mechanism is associated with the first generation agents.

    • There mechanism of action is through neutralizing beta-lactamase enzymes produced by many bacteria, thereby protecting the companion antibiotic’s beta-lactam ring from degradation.¹

      • The five inhibitors discussed here, clavulanic acid, sulbactam, tazobactam, avibactam, and relebactam each enhance the spectrum and efficacy of their associated antibiotics.

    • The β-lactam class of antibiotics, which includes penicillins, cephalosporins, monobactams, and carbapenems, represents the cornerstone of antibacterial therapy and is among the most consequential drug classes in medical history.²

      • Since the discovery of penicillin, these agents have become the most widely prescribed antibiotics globally, accounting for a substantial percentage (≈65%) of all antibiotic usage due to their potent bactericidal activity, broad spectrum, and generally favorable safety profile.^2,3,4 

      • The penicillins mimic the structure of the D-alanyl-D-alanine dipeptide, a key component of bacterial cell walls.

        • This structural similarity allows them to bind covalently to and inactivate essential enzymes known as penicillin-binding proteins (PBPs).

        • PBPs are responsible for the final steps of peptidoglycan synthesis, the rigid polymer that provides structural integrity to the bacterial cell wall.

        • By inhibiting PBP-mediated cross-linking, β-lactams disrupt cell wall maintenance and synthesis, leading to cell lysis and bacterial death.^2,3

    • Diversity of β-lactamases, with thousands of variants identified, required a systematic classification scheme to understand their function and predict their clinical impact.

      • The most widely used system is the Ambler classification, proposed by Richard Ambler in 1980, which groups these enzymes into four major molecular classes (A, B, C, and D) based on their amino acid sequence homology.^6,7

        • This molecular framework aligns closely with the functional properties of the enzymes.

      • Classes A, C, and D:

        • These are known as serine β-lactamases because they utilize a critical serine residue in their active site to initiate hydrolysis of the β-lactam ring. This group contains many of the most clinically challenging enzymes.

          • Class A⁸

            • This class includes the common TEM-1, TEM-2 and HV-1 penicillinases in addition to the extended-spectrum ß-lactamases (ESBLs) like the CTX-M family which can degrade third-generation cephalosporins.

              • This class also includes Klebsiella pneumoniae carbapenemases (KPCs) which inactivate carbapenems.

          • Class C⁸

            • This class consist of AmpC cephalosporinases, which are often chromosomally encoded and can be induced or overexpressed to confer resistance to most cephalosporins.

          • Class D^8,9

            • This class comprises the AmpC cephalosporinases, typically chromosomally encoded, which can be induced or overexpressed thus conferring resistance to most cephalosporins.

              • This class of lactamases which can degrade carbapenems are produced by Pseudomonas aeruginosa, Enterobactericeae and Acinetobacter baumannii.⁸

      • Class B¹⁰

        • Members of this class are metallo-β-lactamases (MBLs), mechanistically distinct from the serine-based enzymes.

          • These enzymes require one or two divalent zinc ions as cofactors in their active site for catalysis. 

            • MBLs, such as NDM, VIM, and IMP types, possess an exceptionally broad hydrolysis spectrum, capable of inactivating nearly all β-lactam antibiotics, including carbapenems.

            • The monobactam aztreonam is an exception.

  • Mechanism of Action

    • All Beta-Lactamase Inhibitors (BLIs) bind to beta-lactamase enzymes, but their exact mechanisms fall into two categories.

      • Clavulanic acid, sulbactam, and tazobactam all have a beta-lactam core and act as classic “suicide inhibitors.”

        • The process involves two steps: (1) acylation of the beta-lactamase active site followed by a secondary reaction (2) that permanently inactivates the enzyme.^1,11  

      • The newer diazabicyclooctane inhibitors, avibactam and relebactam, do not have a beta-lactam core and act as reversible, high-affinity substrates. 

        • Instead of the Beta-Lactam core, these agents feature a diazabicyclooctane (DBO) core.

          • The newer compounds act as reversible covalent inhibitors.

            • These molecules also isolate the active site serine of at target ß-lactamase inactivating the enzyme initially.

            • Since the reaction is reversible,a deacylation reaction occurs generating the original, fully active inhibitor which can then inhibit another beta-lactamase molecule.

        • These newer inhibitors also acylate the enzyme but, upon deacylation, the intact inhibitor is regenerated rather than destroyed (one step).^1,11,13 

          • This reversible covalent binding allows avibactam and relebactam to inactivate multiple enzyme molecules sequentially, making them highly effective against a broad range of serine beta-lactamases.¹¹ 

      • All of these inhibitors are effective against Ambler class A beta-lactamases (e.g. common penicillinases and many extended-spectrum beta-lactamases, ESBLs), and most also inhibit class C (AmpC) enzymes.¹¹ 

        • Avibactam and relebactam additionally have some activity against class D enzymes (such as OXA-48 carbapenemases), though not against class B metallo-beta-lactamases.¹¹   

      • By neutralizing these enzymes, BLIs restore the activity of their partner beta-lactam antibiotics against otherwise resistant bacteria.

August, 2025