Novel Linear Lipopeptide Paenipeptins with Potential for Eradicating Biofilms and Sensitizing Gram-Negative Bacteria to Rifampicin and Clarithromycin

We report the structure–activity relationship analyses of 17 linear lipopeptide paenipeptin analogues. Analogues 7, 12, and 17were more potent than the lead compound. Analogue 17was active against carbapenem-resistant and polymyxin-resistant pathogens. This compound at 40 μg/mL resulted in 3 log and 2.6 log reductions of methicillin-resistant Staphylococcus aureusand Pseudomonas aeruginosa, respectively, in catheter-associated biofilms in vitro. Analogue 17showed little hemolysis at 32 μg/mL and lysed 11% of red blood cells at 64 μg/mL. Analogues 9and 16were nonhemolytic and retained potent P. aeruginosa-specific antimicrobial activity. These two analogues when used alone lacked activity against Acinetobacter baumanniiand Klebsiella pneumoniae; however, analogue 9and 16at 4 μg/mL decreased the MIC of rifampicin and clarithromycin against the same pathogens from 16 to 32 μg/mL to nanomolar levels (sensitization factor: 2048–8192). Therefore, paenipeptins, alone or in combination with rifampicin or clarithromycin, are promising candidates for treating bacterial infections.