Recent advances in the chemistry and biology of carbapenem antibiotics.
The discovery of the olivanic acids and thienamycin aroused considerable interest amongst medicinal chemists and microbiologists around the world. The susceptibility of these agents to metabolic degradation has, however, been a major obstacle in their development. For many years the only notable success from such intensive research was the combination of imipenem with cilastatin, an inhibitor of the renal dipeptidase enzyme DHP-1. The enormous success of Primaxin for the treatment of a range of life-threatening bacterial infections provided the impetus for the discovery of totally synthetic, non-natural carbapenem derivatives that combine the broad spectrum of antimicrobial activity with stability to enzymatic degradation. This has indeed been realised in the development of meropenem; it possesses the broad spectrum of activity and resistance to beta-lactamases that are embodied in imipenem as well as displaying increased stability to human dehydropeptidases. Most recent research has focused upon the development of carbapenem antibiotics which combine broad spectrum antimicrobial activity and metabolic stability with oral absorption, for the treatment of community-acquired infections. Indeed, the pro-drug esters of the tricyclic carbapenems represent the first significant advance in this respect. However, the increased use of carbapenem antibiotics would undoubtedly accelerate the emergence of carbapenem-hydrolysing enzymes. The ultimate challenge could therefore be the design and synthesis of carbapenem derivatives that are resistant to these metallo-beta-lactamases. Due to the enormous problems encountered in the development of the carbapenem antibiotics, this area of research has, in the past, been described as a battlefield that did not bode well for the future [181]. Primaxin and meropenem proved however that these problems were not insurmountable, and are therefore a testimony to the persistence and dedication of those scientists in their war against bacterial infection.
Coulton
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Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, Betchworth, Surrey, U.K.
Hunt
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D001424:Bacterial Infections / Q000188:drug therapy; D015780:Carbapenems / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D004352:Drug Resistance, Microbial; D006801:Humans
D015780:Carbapenems