Evolving Carbapenemases: Can Medicinal Chemists Advance One Step Ahead of the Coming Storm?

Abstract

Carbapenems can be an effective treatment of infections with multidrug-resistant Gram-negative bacteria such as Pseudomonas aeruginosa,1 Acinetobacter spp.,2 Klebsiella pneumoniae,3 and other Enterobacteriaceae.4 They are semi-synthetic or synthetic β-lactam compounds that are distinguished from other β-lactam compounds such as penicillins and cephalosporins by the absence of a sulfur atom in the bicyclic core and a different stereochemistry at Cα of the β-lactam ring (in penicillins and carbapenems, this atom is usually referred to as C6; in cephalosporins as C7) (Figure 1). The most popular carbapenem antibiotics are imipenem5, 6 (Merck, 1985), meropenem7, 8 (Sumitomo Pharmaceuticals and AstraZeneca, 1996), ertapenem9, 10 (Merck, 2005), and doripenem11, 12 (Shionogi Co. and Johnson & Johnson, 2005) (Figure 2). All of these broad-spectrum drugs are used intravenously. Carbapenems are considered to be drugs of last resort due to the fact that they are not inactivated by and effectively inhibit many β-lactamases (most Ambler class A and C β-lactamases13), while these enzymes efficiently hydrolyze penicillins and cephalosporins. β-Lactamases hydrolyze the β-lactam ring of β-lactam antibiotics blocking peptidyltransferase (also referred to as penicillin binding protein or PBP) activity that is critical for the peptidoglycan biosynthesis of the bacterial cell wall.14 β-Lactam antibiotics inhibit peptidyltransferase by forming a stable acyl-enzyme intermediate after an active-site serine of pepdityltransferase cleaves the β-lactam ring through a nucleophilic attack.15 Similar to peptidyltransferase, most β-lactamases contain an active site serine, which exerts a nucleophilic attack on and cleaves the β-lactam ring, resulting in turnover by the enzyme. These enzymes are referred to as serine β-lactamases (SBLs) and, based on sequence and structural homology, have been grouped into classes A, C, and D by Ambler.13 CTX-M β-lactamases are a group of class A SBLs expressed by Enterobacteriaceae that confer resistance toward the third-generation cephalosporin cefotaxime (Figure 3).16 As a consequence, carbapenems are frequently used to treat infections with Enterobacteriaceae expressing these enzymes. The increased use of carbapenems drives the emergence of carbapenem resistance mechanisms. Open in a separate window Figure 1 Chemical structures of the bicyclic cores of different classes of β-lactam antibiotics. The penem core is found in penicillins and consists of a β-lactam ring fused with a tetrahydrodrothiazole ring. The cephem core is found in cephalosporins and consists of a β-lactam ring fused with a dihydrothiazine ring. The carbapenem core consists of a β-lactam ring fused with a dihydropyrrole ring. Heavy atoms of the bicyclic systems are numbered according to common use rather than according to the IUPAC nomenclature to facilitate comparisons between the different antibiotics. Note that the numbering of the R groups is arbitrary; here we started labeling R groups from the ones attached to the core atoms with the lowest number.