Dilipid Ultrashort Tetrabasic Peptidomimetics (dUSTBPs) Potentiate Novobiocin and Rifampicin Against Multidrug-resistant Gram-negative Bacteria.

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Dilipid Ultrashort Tetrabasic Peptidomimetics (dUSTBPs) Potentiate Novobiocin and Rifampicin Against Multidrug-resistant Gram-negative Bacteria.

ACS Infect Dis. 2020 May 01;:

Authors: Ramirez D, Berry L, Domalaon R, Brizuela M, Schweizer FM

Abstract
The development of new antibacterial agents and therapeutic approaches is of high importance to combat the global problem of antibiotic resistance. Although antimicrobial peptides offer insights as adjuvant partners to existing antibiotics, their clinical application is limited by their systemic toxicity, protease instability, and high production cost. To overcome these problems, nine dilipid ultrashort tetrabasic peptidomimetics (dUSTBPs) were prepared consisting of three basic amino acids separated by the molecular scaffold, bis(3-aminopropyl)glycine, and are ligated to two fatty acids. Several non-hemolytic dUSTBPs were shown to potentiate activity against Gram-negative bacteria of several antibiotics. More importantly, compound 8, consisting of three L-arginine units and a dilipid of 8 carbons-long, potentiated rifampicin and novobiocin consistently against multidrug-resistant (MDR) clinical isolates of Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacteriaceae. Preliminary studies showed that dUSTBPs were likely to potentiate antibiotics through outer membrane permeabilization and/or disruption of active efflux, and that dUSTBP 8 exhibited enhanced resistance to trypsin in comparison to di-C9-KKKK-NH2. Our data revealed that the degree of potentiation of rifampicin and novobiocin by dUSTBP 8 was comparable to other known outer membrane permeabilizing agents including the gold standard polymyxin B nonapeptide. Our results indicate that polybasic peptidomimetic-based adjuvants repurpose novobiocin and rifampicin as potent agents against priority MDR Gram-negative pathogens.

PMID: 32357292 [PubMed - as supplied by publisher]