An Optimized Synthetic-Bioinformatic Natural Product Antibiotic Sterilizes Multidrug-Resistant -Infected Wounds.

The antibiotic paenimucillin A was originally identified using a culture-independent synthetic-bioinformatic natural product (syn-BNP) discovery approach. Here we report on a bioinformatics-guided survey of paenimucillin A analogs that led to the discovery of paenimucillin C. Paenimucillin C inhibits the growth of multidrug-resistant (MDR) clinical isolates, as well as other Gram-negative bacterial pathogens. In a rat cutaneous wound model, it completely sterilized MDR wound infections with no sign of rebound. Mechanistic studies point to a membrane-associated mode of action that results in leakage of intracellular contents. Natural product-inspired antibiotics have saved millions of lives and played a critical role in modern medicine. However, the emergence of drug-resistant pathogens is outpacing the rate at which new clinically useful antibiotics are being discovered. The lack of a means to combat infections caused by multidrug-resistant (MDR) is of particular concern. The sharp increase in cases of MDR infections in recent years prompted the CDC (https://www.cdc.gov/drugresistance/biggest_threats.html) and WHO (http://www.who.int/medicines/publications/global-priority-list-antibiotic-resistant-bacteria/en/) to list this pathogen as a "serious threat" and "critical pathogen," respectively. Here we report a new antibiotic, paenimucillin C, active against Gram-negative bacterial pathogens, including many clinical isolates of MDR strains. Mechanistic studies point to membrane disruption leading to leakage of intracellular contents as its antibacterial mode of action. Paenimucillin C sterilizes MDR infections in a rat cutaneous wound model with no sign of rebound infection, providing a potential new therapeutic regimen.