Regulation and biosynthesis of carbapenem antibiotics in bacteria

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Abstract
Members of the β-lactam family of antibiotics (penicillins, cephalosporins/cephamycins, monobactams, clavams and carbapenems) function by interfering with bacterial cell wall biosynthesis and are in widespread clinical use for the treatment of bacterial infections. Carbapenems are of particular interest because they are often resistant to the many β-lactamase enzymes that are produced by clinically important bacterial pathogens. β-lactamases commonly confer resistance to penicillin and cephalosporin-related antibiotics. Carbapenem-producing organisms include Streptomyces cattleya, which produces thienamycin, and a few Gram-negative bacterial species, including Erwinia carotovora subsp. carotovora, Serratia sp. strain ATCC39006 and Photorhabdus luminescens, which all produce Car (1-carbapen-2-em-3-carboxylic acid). The E. c. carotovora and Serratia ATCC39006 carA–H biosynthetic operons encode genes that are involved in Car biosynthesis (carA–E) and genes that are required for the Car resistance mechanism (carF and carG). Expression of the carA–H operon in E. c. carotovora and Serratia ATCC39006 is regulated by the Hor/Rap transcriptional regulators, respectively. Expression is also regulated by quorum sensing (cell density-dependent) control in both bacteria — although the underlying mechanisms are different. Physiological cues that affect Car production in Erwinia spp. include temperature, oxygen availability and carbon source. The core biosynthetic enzymes are CarA (carbapenam synthetase), CarB (carboxymethylproline synthase) and CarC (carbapenem synthase). CarB (similar to enoyl coenzyme A (CoA) hydratase enzymes) condenses malonyl-CoA and glutamate semialdehyde to form (2S,5S)-carboxymethyl proline (CMP), which is the substrate for the CarA enzyme. CarA catalyses the ATP-dependent formation of (3S,5S)-carbapenam from CMP, resulting in the closure of the β-lactam ring. Finally, CarC acts on the carbapenam product of CarA to introduce a double bond and to produce a stereoinversion, thereby forming the active molecule, carbapenem. Homologues of CarA and CarC (β-lactam synthetase and clavaminate synthase, respectively) function in clavulanic acid biosynthesis in Streptomyces clavuligerus, and the Car and clavulanate biosynthesis pathways have some similarities. Putative homologues of carA (thnM) and carB (thnE) have been found in the thnA–V operon required for thienamycin biosynthesis in S. cattleya, and a biosynthetic pathway for thienamycin has been proposed. An improved understanding of carbapenem biosynthesis might pave the way towards the development of novel carbapenems that have useful chemotherapeutic activities.