Dioctanoyl Ultrashort Tetrabasic β-Peptides Sensitize Multidrug-Resistant Gram-Negative Bacteria to Novobiocin and Rifampicin

Recently reported peptidomimetics with increased resistance to trypsin were shown to sensitize priority multidrug-resistant (MDR) Gram-negative bacteria to novobiocin and rifampicin. To further optimize proteolytic stability, β-amino acid-containing derivatives of these compounds were prepared, resu...

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Published inFrontiers in microbiology Vol. 12; p. 803309
Main Authors Ramirez, Danyel, Berry, Liam, Domalaon, Ronald, Li, Yanqi, Arthur, Gilbert, Kumar, Ayush, Schweizer, Frank
Format Journal Article
LanguageEnglish
Published Switzerland Frontiers Media S.A 23.12.2021
Subjects
antibiotic adjuvant
Microbiology
novobiocin
peptidomimetic
Pseudomonas aeruginosa
rifampicin
β-amino acid
rifampicin
Acinetobacter baumannii
novobiocin
Escherichia coli
β-amino acid
Pseudomonas aeruginosa
antibiotic adjuvant
peptidomimetic
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Summary:Recently reported peptidomimetics with increased resistance to trypsin were shown to sensitize priority multidrug-resistant (MDR) Gram-negative bacteria to novobiocin and rifampicin. To further optimize proteolytic stability, β-amino acid-containing derivatives of these compounds were prepared, resulting in three dioctanoyl ultrashort tetrabasic β-peptides (dUSTBβPs). The nonhemolytic dUSTBβP 3, comprised of three β -homoarginine residues and two fatty acyl tails eight carbons long, enhanced the antibacterial activity of various antibiotics from different classes. Notably, compound 3 retained the ability to potentiate novobiocin and rifampicin in wild-type Gram-negative bacteria against MDR clinical isolates of , , , , and . dUSTBβP 3 reduced the minimum inhibitory concentration of novobiocin and rifampicin below their interpretative susceptibility breakpoints. Furthermore, compound 3 exhibited improved stability (86.8 ± 3.7% remaining) relative to its α-amino acid-based counterpart (39.5 ± 7.4% remaining) after a 2 h incubation in human plasma.
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Edited by: Wang Jiajun, Northeast Agricultural University, China
Reviewed by: Henrik Franzyk, University of Copenhagen, Denmark; Kevin Bicker, Middle Tennessee State University, United States
This article was submitted to Antimicrobials, Resistance and Chemotherapy, a section of the journal Frontiers in Microbiology
ISSN:1664-302X
1664-302X
DOI:10.3389/fmicb.2021.803309