AUTHOR=Ramirez Danyel , Berry Liam , Domalaon Ronald , Li Yanqi , Arthur Gilbert , Kumar Ayush , Schweizer Frank 

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

JOURNAL=Frontiers in Microbiology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2021.803309

DOI=10.3389/fmicb.2021.803309

ISSN=1664-302X

ABSTRACT=<p>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<sup>3</sup>-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 <italic>Pseudomonas aeruginosa</italic>, <italic>Acinetobacter baumannii</italic>, <italic>Escherichia coli</italic>, <italic>Klebsiella pneumoniae</italic>, and <italic>Enterobacter cloacae</italic>. dUSTBβP 3 reduced the minimum inhibitory concentration of novobiocin and rifampicin below their interpretative susceptibility breakpoints. Furthermore, compound 3 exhibited improved <italic>in vitro</italic> 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.</p>