Recent advances and perspectives in the design and development of polymyxins

The rise of bacterial pathogens with acquired resistance to almost all available antibiotics is becoming a serious public health issue. Polymyxins, antibiotics that were mostly abandoned a few decades ago because of toxicity concerns, are ultimately considered as a last-line therapy to treat infections caused by multi-drug resistant Gram-negative bacteria. This review surveys the progress in understanding polymyxin structure, and their chemistry, mechanisms of antibacterial activity and nephrotoxicity, biomarkers, synergy and combination with other antimicrobial agents and antibiofilm properties. An update of recent efforts in the design and development of a new generation of polymyxin drugs is also discussed. A novel approach considering the modification of the scaffold of polymyxins to integrate metabolism and detoxification issues into the drug design process is a promising new line to potentially prevent accumulation in the kidneys and reduce nephrotoxicity.