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

Danyel Ramirez; Liam Berry; Ronald Domalaon; Yanqi Li; Gilbert Arthur; Ayush Kumar; Frank Schweizer

doi:10.3389/fmicb.2021.803309

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

Front Microbiol. 2021 Dec 23:12:803309. doi: 10.3389/fmicb.2021.803309. eCollection 2021.

Authors

Danyel Ramirez¹, Liam Berry¹, Ronald Domalaon¹, Yanqi Li², Gilbert Arthur³, Ayush Kumar², Frank Schweizer^{1

4}

Affiliations

¹ Department of Chemistry, University of Manitoba, Winnipeg, MB, Canada.
² Department of Microbiology, University of Manitoba, Winnipeg, MB, Canada.
³ Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada.
⁴ Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada.

Abstract

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 β³-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 Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae. dUSTBβP 3 reduced the minimum inhibitory concentration of novobiocin and rifampicin below their interpretative susceptibility breakpoints. Furthermore, compound 3 exhibited improved in vitro 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.

Keywords: Acinetobacter baumannii; Escherichia coli; Pseudomonas aeruginosa; antibiotic adjuvant; novobiocin; peptidomimetic; rifampicin; β-amino acid.