Abstract
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) Acinetobacter baumannii clinical isolates, as well as other Gram-negative bacterial pathogens. In a rat cutaneous wound model, it completely sterilized MDR A.baumannii wound infections with no sign of rebound. Mechanistic studies point to a membrane-associated mode of action that results in leakage of intracellular contents. IMPORTANCE 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) Acinetobacter baumannii is of particular concern. The sharp increase in cases of MDR A.baumannii 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 A.baumannii strains. Mechanistic studies point to membrane disruption leading to leakage of intracellular contents as its antibacterial mode of action. Paenimucillin C sterilizes MDR A.baumannii infections in a rat cutaneous wound model with no sign of rebound infection, providing a potential new therapeutic regimen.
Highlights
The antibiotic paenimucillin A was originally identified using a cultureindependent synthetic-bioinformatic natural product discovery approach
We identified a series of antibiotics inspired by bioinformatic analysis of nonribosomal peptide synthetase (NRPS) gene clusters
A pair of these initial antibacterial synthetic-bioinformatic natural product (syn-BNP), paenimucillin A and B (1F and 1W [Fig. 2]), are closely related N-acylated 13-mer linear peptides containing seven D-amino acids and three nonproteinogenic residues [10]. Both syn-BNPs were synthesized based on bioinformatic predictions arising from an NRPS gene cluster found in the genome of Paenibacillus mucilaginosus K02 [11, 12]
Summary
The antibiotic paenimucillin A was originally identified using a cultureindependent synthetic-bioinformatic natural product (syn-BNP) discovery approach. Paenimucillin C inhibits the growth of multidrug-resistant (MDR) Acinetobacter baumannii clinical isolates, as well as other Gram-negative bacterial pathogens. The lack of a means to combat infections caused by multidrug-resistant (MDR) Acinetobacter baumannii is of particular concern. We report a new antibiotic, paenimucillin C, active against Gram-negative bacterial pathogens, including many clinical isolates of MDR A. baumannii strains. Paenimucillin C sterilizes MDR A. baumannii infections in a rat cutaneous wound model with no sign of rebound infection, providing a potential new therapeutic regimen. A number of recent reports have found that the absence of antibiotics capable of controlling multidrug-resistant (MDR) infections caused by the opportunistic Gram-negative pathogen Acinetobacter baumannii is of particular concern [2, 3]. New means of identifying NPs or NP-like antibiotics capable of combating antibioticresistant pathogens are needed to circumvent this bottleneck
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