Short proline-rich lipopeptide potentiates minocycline and rifampicin against multidrug- and extensively drug-resistant Pseudomonas aeruginosa. [PublishAheadOfPrint]

A series of 16 short proline-rich lipopeptides (SPRLPs) were constructed to mimic longer naturally-existing proline-rich antimicrobial peptides. Antibacterial assessment revealed that lipopeptides containing hexadecanoic acid (C16) possess optimal antibacterial activity relative to others with shorter lipid component. SPRLPs were further evaluated for their potential to serve as adjuvants in combination with existing antibiotics to enhance antibacterial activity against drug-resistant Pseudomonas aeruginosa. Out of sixteen prepared SPRLPs, C12-PRP was found to significantly potentiate the antibiotics minocycline and rifampicin against multidrug- and extensively drug-resistant (MDR/XDR) P. aeruginosa clinical isolates. This non-hemolytic C12-PRP is comprised of a heptapeptide sequence PRPRPRP-NH₂ acylated to dodecanoic acid (C12) at the N-terminus. The adjuvant potency of C12-PRP was apparent by its ability to reduce the minimum inhibitory concentration of minocycline and rifampicin below their interpretative susceptibility breakpoints against MDR/XDR P. aeruginosa. An attempt to optimize C12-PRP through peptidomimetic modification was performed by replacing all L- to D-amino acids. C12-PRP demonstrated pliability to optimization as synergism with minocycline and rifampicin were retained. Moreover, C12-PRP displayed no cytotoxicity against human liver carcinoma HepG2 and human embryonic kidney HEK-293 cell lines. Thus, the SPRLP C12-PRP is a lead adjuvant candidate that warrants further optimization. Discovery of agents that are able to resuscitate activity of existing antibiotics against drug-resistant Gram-negative pathogens, especially P. aeruginosa are of great clinical interest.

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