This document discusses beta lactamase inhibitors, which are used to enhance the efficacy of beta lactam antibiotics like penicillins and cephalosporins. It describes how beta lactamase enzymes produced by bacteria provide resistance to these antibiotics by breaking their beta lactam ring structure. Beta lactamase inhibitors prevent this degradation by binding to and inactivating the beta lactamase enzymes. There are two classes of inhibitors - those with a beta lactam core like clavulanic acid and those without, such as avibactam. Inhibitors are used in combination with beta lactams to treat infections that may involve beta lactamase producing bacteria.

1. BETA LACTAMASE INHIBITORS

2. Introduction
Beta-lactamases are enzymes (EC 3.5.2.6) produced by bacteria that provide multi- resistance to β-lactam
antibiotics such as penicillins, cephalosporins, cephamycins, and carbapenems (ertapenem). Beta-lactamase
provides antibiotic resistance by breaking the antibiotics' structure.
These antibiotics all have a common element in their molecular structure: a four-atom ring known as a β-
lactam. Through hydrolysis, the enzyme lactamase breaks the β-lactam ring open, deactivating the molecule's
antibacterial properties.
Beta-lactam antibiotics are typically used to treat a broad spectrum of Gram-positive and Gram-negative
bacteria. Beta-lactamases produced by Gram-negative organisms are usually secreted, especially when
antibiotics are present in the environment.

4. C

5. Beta lactamases can be classified into 4 distinct classes termed: A, B, C and D. A further fundamental division
is between the three classes (A, C and D) of active site serine enzymes (serine beta lactamases) and class B
that comprises of a heterogenous group of zinc metalloenzymes (metallo beta lactamases).
Class A: Enzymes from gram positive bacteria (e.g., penicillinase).
Class B: Broad spectrum metallo-enzymes which mainly hydrolyse carbapenems.
Class C: Enzymes from gram negative bacteria (cephalosporinase).
Class D: Hydrolyse more beta lactamase stable isoxazyl penicillins.

6. Beta lactamase producing bacteria
Bacteria that can produce beta-lactamases include, but are not limited to:
Staphylococcus
MRSA (Methicillin-resistant Staphylococcus aureus)
Enterobacteriaceae:
Klebsiella pneumoniae
Citrobacter
Proteus vulgaris
Morganella

7. Salmonella
Shigella
Escherichia coli
Haemophilus influenzae
Neisseria gonorrhoeae
Pseudomonas aeruginosa
Mycobacterium tuberculosis

8. Beta lactamase inhibitors
Beta lactamase inhibitors block the beta lactamase enzymes and enhance the efficacy of their partner beta
lactamases (e.g., amoxycillin, ampicillin, piperacillin, cefoperazone, and ticarcillin) in the treatment of serious
infections.
Beta lactamase inhibitors have very little antibiotic activity of their own, they prevent bacterial degradation
of the beta lactam antibiotics (such as penicillins and cephalosporins) and thus extend the range of bacteria
the drugs are effective against.

9. Classification
1. Beta lactamase inhibitors with a beta lactam core:
Tebipenem (tebipenem-pivoxil) (brand name Orapenem)

10. Clavulanic acid (or clavulanate, usually combined with amoxicillin (Augmentin) or ticarcillin (Timentin))
Sulbactam (usually combined with ampicillin (Unasyn) or cefoperazone (Sulperazon))

11. Tazobactam (usually combined with piperacillin (Zosyn and Tazocin))

12. 2. Beta lactamase inhibitors without a beta lactam core:
Avibactam (approved in combination with ceftazidime (Avycaz), currently undergoing clinical trials for
combination with ceftaroline)

13. Relebactam (used in combination with imipenem/cilastatin (Recarbrio))
Vaborbactam (used in combination with meropenem (Vabomere))

15. Mechanism of action
All the beta lactamase inhibitors bind to the beta lactamase enzyme and inactivate them (act as suicide
substrates).
Inhibitors with beta lactam core (e.g., clavulanic acid) are processed by beta lactamases to form an initial
covalent intermediate and bind reversibly with the enzyme which ultimately leads to the degradation of beta
lactamase.

17. Inhibitors without a beta lactam core (e.g., avibactam) binds reversibly with the enzyme (covalent bond)-
covalent acylation of the serine residue of the beta lactamase enzyme.
Vaborbactam forms reversible dative bond with the beta lactamase (between catalytic serine and boronate
moiety).

18. Video:
https://www.youtube.com/watch?v=iSe-GmywF7M

19. Therapeutic Uses
Beta lactamase inhibitors are used in combination with other beta lactam antibiotics such as penicillins and
cephalosporins for the treatment of severe infections known or believed to be caused by gram negative
bacteria.
Sinus infection
Urinary tract infection
Pyelonephritis
Pelvic infection
Respiratory infection
Intra-abdominal infections
Dental infections

20. Structure Activity Relationships
All the beta lactamase inhibitors should essentially contain a beta lactam ring, e.g., calvulanic acid, sulbactam,
tazobactam.
Any modification in the beta lactam ring ring result in loss of activity.
Removal/ replacement of hetero N-atom by any other atom (such as C, S, or O) result in loss of activity.
Removal of C=O bond results in new compounds with reduced activity.
Free carboxylic acid group is essential for the inhibitor activity.

21. Clavulanic acid
Sulbactam

22. Tazobactam

23. Adverse Effects
Severe skin rash.
Itching.
Hives.
Difficulty breathing or swallowing.
Wheezing.
Yellowing of the skin or eyes.