Short Proline-Rich Lipopeptide Potentiates Minocycline and Rifampin against Multidrug- and Extensively Drug-Resistant Pseudomonas aeruginosa

Abstract

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 (C) possess optimal antibacterial activity relative to others with shorter lipid components. SPRLPs were further evaluated for their potential to serve as adjuvants in combination with existing antibiotics to enhance antibacterial activity against drug-resistant Out of 16 prepared SPRLPs, C-PRP was found to significantly potentiate the antibiotics minocycline and rifampin against multidrug- and extensively drug-resistant (MDR/XDR) clinical isolates. This nonhemolytic C-PRP is comprised of the heptapeptide sequence PRPRPRP-NH acylated to dodecanoic acid (C) at the N terminus. The adjuvant potency of C-PRP was apparent by its ability to reduce the MIC of minocycline and rifampin below their interpretative susceptibility breakpoints against MDR/XDR An attempt to optimize C-PRP through peptidomimetic modification was performed by replacing all l- to d-amino acids. C-PRP demonstrated that it was amenable to optimization, since synergism with minocycline and rifampin were retained. Moreover, C-PRP displayed no cytotoxicity against human liver carcinoma HepG2 and human embryonic kidney HEK-293 cell lines. Thus, the SPRLP C-PRP is a lead adjuvant candidate that warrants further optimization. The discovery of agents that are able to resuscitate the activity of existing antibiotics against drug-resistant Gram-negative pathogens, especially , is of great clinical interest.

Evaluation of the Synergistic Effect of Amikacin with Cefotaxime against Pseudomonas aeruginosa and Its Biofilm Genes Expression

“…Interpretative reading was used to detect the bactericidal activity of each antibiotic against isolates with cefotaxime MICs of 8-512 and amikacin MICs of 1-64. These data are reinforced by findings from other countries, including Kuwait [37], Canada [38], China [39], and the USA [40].…”

Microbial biosurfactants: current trends and applications in agricultural and biomedical industries

“…Domalaon et al . () in their investigation of short proline‐rich LPs revealed an amphiphilic nonhaemolytic noncytotoxic L‐LP that significantly potentiated the activity of minocycline and rifampicin against multidrug‐resistant MDR and XDR clinical isolates of Pseudomonas aeruginosa . Ghribi and Ellouze‐Chaabouni () isolated a biosurfactant‐producing strain B. subtilis SPB1 (HQ392822) and identified antimicrobial activity against micro‐organisms with multidrug‐resistant profiles (Ghribi et al .…”

Antimicrobial peptides: Promising alternatives in the post feeding antibiotic era

“…Lipid tail length has a great influence on the antimicrobial activity and hemolysis of peptides/peptoids, mainly because the lipid tail length is closely related to the molecular hydrophobicity . Furthermore, some lipopeptides/lipopeptoids also have strong synergistic activities with conventional antibiotics, possess anticancer activity, induce cytokine production in macrophages and exert immunomodulating properties . The mechanism of action of lipopeptides/lipopeptoids has been extensively and deeply studied in recent years, such as that of Tridecaptin A1 (TriA1), which is a nonribosomal lipopeptide with selective antimicrobial activity against Gram‐negative bacteria.…”