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.
Highlights
Antimicrobial resistance is a major threat to the global healthcare system that has caused a lack of treatment options for challenging bacterial infections (Prestinaci et al, 2015)
Examples include β-lactamase inhibitors that prevent the enzymatic degradation of β-lactam antibiotics (Drawz and Bonomo, 2010), bacterial efflux pump inhibitors (Lamers et al, 2013), and outer membrane (OM)-permeabilizing agents derived from cationic antimicrobial peptides (AMPs)
Compound 3 was shown to possess enhanced plasma stability relative to its α-amino acid-based counterpart di(C8-Arg)-NbapArg-NH2. These results indicate that multiple peptidomimetic approaches can serve to further improve proteolytic resistance of AMPs without compromising adjuvant activity
Summary
Antimicrobial resistance is a major threat to the global healthcare system that has caused a lack of treatment options for challenging bacterial infections (Prestinaci et al, 2015). Antimicrobial resistance can occur through several distinct mechanisms, including efflux, reduced antibiotic membrane penetration, modification of antibiotic targets, and the production of enzymes to degrade antibiotics (Reygaert, 2018). Examples include β-lactamase inhibitors that prevent the enzymatic degradation of β-lactam antibiotics (Drawz and Bonomo, 2010), bacterial efflux pump inhibitors (Lamers et al, 2013), and OM-permeabilizing agents derived from cationic antimicrobial peptides (AMPs). Membrane-permeabilizing adjuvants derived from the polymyxin family of AMPs have seen some pre-clinical success. Spero Therapeutics is presently developing SPR741, an adjuvant derived from PMBN, which has reduced toxicity and improved pharmacokinetics (Eckburg et al, 2019; Vaara, 2019). Various short cationic lipopeptide adjuvants have been reported that display similar membrane permeabilizing properties (Domalaon et al, 2018a,b, 2019a; Ramirez et al, 2020)
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