Polymyxins are the last resort in the therapy of infections caused by extremely multiresistant Gram-negative bacteria. However, their nephrotoxicity may complicate the therapy or even require its discontinuation. Whether new derivatives are less toxic in relevant animal models in vivo than older polymyxins remains to be seen. The future will also show whether resistance to polymyxins will evolve to limit their use. The use of polymyxin compounds in combination with another antibiotic may reduce the risk of resistance developing. We need to be very careful with our remaining drugs of last resort.
Polymyxins and their novel derivatives. Curr Opin Microbiol. Sep 23 2010
The emerging very multiresistant Gram-negative bacteria cause remarkable therapeutic challenges. There are no novel classes of agents in clinical development for the treatment of Gram-negative infections. Polymyxins such as polymyxin B and colistin were abandoned in the seventies but are now back in the therapy as the last resort. Their nephrotoxicity may complicate the therapy or even necessitate its discontinuation. Less toxic polymyxin derivatives would be highly welcome. Novel derivatives lack in strategic positions two of the five cationic charges of polymyxins, differ from polymyxins in their renal handling and affinity to kidney brush-border membrane, and are in preclinical studies. Less characterized other recent derivatives, also reviewed here, have increased the collective knowledge on the structure-function relationships in polymyxins. Acquired resistance to polymyxins has been encountered. However, the resistance mechanism compromises the function of the bacterial outer membrane as a permeability barrier to other noxious agents.
- Designer drugs for discerning bugs. PNAS USA September 27 2010,. doi: 10.1073/pnas.101254710
- Domagk, Fleming, Waksman and the Third Man
- The Good, the Bad and the Ugly of Antibiotics