Abstract
The emergence of multidrug-resistant pathogens presents a major clinical challenge worldwide. The underexplored bacterial genus Aquimarina harbors a large biosynthetic potential for the discovery of new classes of antibiotics with distinctive modes of action, which can be unearthed in a scalable manner using a synthetic bioinformatic natural product approach. Here, the discovery of a pair of linear or cyclic bifunctional cationic lipopeptide antibiotics, aquicidine L and aquicidine C4, with opposite antibacterial spectra, is reported, which are chemically synthesized on the basis of distinct structure prediction of the aquicidine gene cluster from Aquimarina. Aquicidine L mainly targets both anionic lipopolysaccharide and phosphatidylethanolamine in the bacterial membrane and is efficacious against two different meropenem-resistant Gram-negative pathogens in murine peritonitis-sepsis models. In contrast, aquicidine C4 mainly binds to both anionic cardiolipin and phosphatidylglycerol in the membrane and proves effective at treating methicillin- or vancomycin-resistant Gram-positive pathogen infections in vivo. Owing to the dual-mechanism features of aquicidine L or aquicidine C4, both of them are absent in detectable resistance in laboratory tests. These findings provide a pair of naturally inspired and mechanistically interesting therapeutic leads for evading antimicrobial resistance.