New molecules from old classes: revisiting the development of beta-lactams.
Beta-lactams are among the most successful classes of antibiotics, both medically and commercially. However, more than 60 years of extensive, and sometimes inappropriate, use has enabled bacteria to develop a broad range of resistance mechanisms. Nevertheless, the versatility of the beta-lactam core structure, combined with the innovation of medicinal chemists, has repeatedly led to the development of new generations of beta-lactam antibiotics that are capable of overcoming the problems caused by mounting bacterial resistance. In particular, two cephalosporin derivatives, ceftobiprole and ceftaroline (Forest Laboratories Inc/AstraZeneca plc), as well as the carbapenem razupenem (Novartis AG/Dainippon Sumitomo Pharma Co Ltd), have demonstrated potent activity against the gram-positive 'superbug' MRSA. CXA-101 (Calixa Therapeutics Inc) is a new member of the series of cephalosporins that are effective against gram-negative bacteria such as Pseudomonas aeruginosa. The compound has been demonstrated to be particularly stable to degradation by the class C beta-lactamases in P. aeruginosa. Furthermore, siderophore-containing monobactams such as BAL-30072 (Basilea Pharmaceutica International Ltd) are inherently stable to hydrolysis by metallo-beta-lactamases, and act as 'Trojan horses' by being transported into gram-negative cells using endogenous bacterial iron-uptake systems. Considering the significant medical need for novel antibiotics that are active against resistant strains of bacteria, it is hoped several of the new generation of beta-lactam compounds that are in clinical development will soon reach the market.
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Malcolm G P
MG
Basilea Pharmaceutica International Ltd, Grenzacherstrasse 487, CH-4005 Basel, Switzerland. malcolm.page@basilea.com
Heim
Jutta
J
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002511:Cephalosporins / Q000494:pharmacology; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D047090:beta-Lactams / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D047090:beta-Lactams