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Background

OXA-24 is a member of the carbapenem-hydrolyzing class D β-lactamases (CHDLs), and is expressed as a resistance mechanism by the bacteria, Acinetobacter baumannii. Class D β-lactamases are clinically dangerous because they hydrolyze β-lactam antibiotics, such as penicillins, cephalosporins, and carbapenems. Class D β-lactamases are classified as OXA’s, in reference to their class designation as oxacillinases. The terminology is somewhat misleading; while they do have very strong affinity for the antibiotic oxacillin^[3], the OXA’s have expanded since their discovery to include penillinase, cephalosporinase, and carbapenemase activity in their spectrum. However, due to their original designation as oxacillinases, the assignment of the prefix OXA has continued to be standard designation.

Bacterial Resistance

Since the discovery of penicillin by Alexander Flemming in 1928, antibiotics have revolutionized the medical world. Penicillin is known as a β-lactam antibiotic, which is characterized by a four-membered β-lactam ring (a cyclic amide). There are four classes of β-lactam antibiotics: monobactams, which are the simplest class of β-lactam, and aren’t fused to any rings, penicillins, which have a thiazole ring fused to the β-lactam, cephalosporins which contain a thiazine ring, and lastly, carbapenems, which are fused with a pyrrole ring and are considered a last line of defense. ^[4] β-lactam antibiotics are the most widely used class of antibiotics because they successfully fight most bacterial infections by inhibiting cell wall synthesis. Their mechanism of action is through inhibition of the transpeptidas enzymes, located in the bacterial cell membrane. Transpeptidase is alternatively referred to as a penicillin-binding protein (PBP) and is responsible for catalyzing the cross-linking of the bacterial cell wall ^[5]. β-lactams mimic the structure of the terminal D-alanine chain of peptidoglycan and irreversibly bind to PBP, disrupting the cross-linking process that is critical to cell wall synthesis. As a result, the bacterial cell wall is compromised, and the bacteria lyse and die.^[6]

Due to overperscription and misuse of antibiotics, bacteria have been able to develop resistance mechanisms. One of these resistance mechanisms is through the expression of β-lactamases, which have evolved as a seperate enzyme over millions of years from PBP.^[7] β-lactamases act by hydrolyzing the β-lactam ring, which renders the antibiotic inactive before it has a chance to inhibit the transpeptidase enzymes.^[8] β-lactamases are grouped into four different classes (A, B, C and D), which all (besides class B) use a serine based mechanism for destruction of β-lactams. Class B β-lactamases use zinc ions for hydrolysis. Class D was distinguished from other serine β-lactamases in the late 1980s, due to having an affinity for oxacillin as its substrate in addition to other antibiotics.^[9] Even more concerning is that the class D β-lactamases, or OXAs, are not inhibited by current clinical β-lactamase inhibitors, such as clavulanic acid. OXA-24, which has considerable carbapenemase activity, poses a dangerous clinical threat due to the absence of an effective inhibitor.

CHDLs

Structure

Hydrolysis Mechanism

β-lactam antibiotics (basic structure of a β-lactam is shown above) are hydrolyzed by β-lactamase enzymes, utilizing a covalent catalysis serine-based mechanism. The β-lactamase cleaves the amide bond of the four membered ring which renders the antibiotic inactive before it reaches its bacterial target, the transpeptidase enzymes.

The mechanism of attack involves a catalytic serine residue, a carboxylated lysine, and another active site serine which contributes to proton movement (A). A high energy tetrahedral intermediate (B) is generated and an acyl enzyme intermediate (C) is formed after the cleavage of the four-membered ring. KCX84 activates the deacylating water which completes the reaction leaving a hydrolyzed β-lactam ring and a regenerated β-lactamase.^[10]

^[11]

Inhibition

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