Effects of Lysine N-ζ-Methylation in Ultrashort Tetrabasic Lipopeptides (UTBLPs) on the Potentiation of Rifampicin, Novobiocin, and Niclosamide in Gram-Negative Bacteria.

Linus Schweizer,Danyel Ramirez,Frank Schweizer

doi:10.3390/antibiotics11030335

Linus Schweizer, Danyel Ramirez + Show 1 more

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https://doi.org/10.3390/antibiotics11030335

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Journal: Antibiotics	Publication Date: Mar 3, 2022
Citations: 9	License type: CC BY 4.0

Affiliation: University of Toronto, University of Manitoba

Abstract

Outer membrane (OM) drug impermeability typically associated with a molecular weight above 600 Da and high hydrophobicity prevents accumulation of many antibiotics in Gram-negative bacteria (GNB). Previous studies have shown that ultrashort tetrabasic lipopeptides (UTBLPs) containing multiple lysine residues potentiate Gram-positive bacteria (GPB)-selective antibiotics in GNB by enhancing OM permeability. However, there is no available information on how N-substitution at the ζ-position of lysine in UTBLPs affects antibiotic potentiation in GNB. To study these effects, we prepared a series of branched and linear UTBLPs that differ in the degree of N-ζ-methylation and studied their potentiating effects with GPB-selective antibiotics including rifampicin, novobiocin, niclosamide, and chloramphenicol against wild-type and multidrug-resistant GNB isolates. Our results show that increasing N-ζ-methylation reduces or abolishes the potentiating effects of UTBLPs with rifampicin, novobiocin, and niclosamide against GNB. No trend was observed with chloramphenicol that is largely affected by efflux. We were unable to observe a correlation between the strength of the antibiotic potentiating effect to the increase in fluorescence in the 1-N-phenylnaphthylamine (NPN) OM permeability assay suggesting that other factors besides OM permeability of NPN play a role in antibiotic potentiation. In conclusion, our study has elucidated crucial structure–activity relationships for the optimization of polybasic antibiotic potentiators in GNB.

Highlights

Bacterial resistance to antibiotics is a major global health problem [1]
Carbapenem-resistant Pseudomonas aeruginosa (CRPA), carbapenem-resistant Acinetobacter baumannii (CRAB), and carbapenem-resistant Enterobacteriaceae (CRE) are among the priority pathogens that pose the greatest threat to human health [2,3]
Our results demonstrate a clear trend in the potentiating power of the various ultrashort tetrabasic lipopeptides (UTBLPs) in combination with Gram-positive bacteria (GPB)-selective antibiotics (Figure 2)

Summary

Introduction

Carbapenem-resistant Pseudomonas aeruginosa (CRPA), carbapenem-resistant Acinetobacter baumannii (CRAB), and carbapenem-resistant Enterobacteriaceae (CRE) are among the priority pathogens that pose the greatest threat to human health [2,3] These Gram-negative bacteria (GNB) are frequently multidrug-resistant (MDR) and have become resistant to most antibiotics. Despite large investments into antibiotic discovery, no new drug class with novel modes of action against GNB has been approved in 50 years [4,5] This failure is caused by intrinsic resistance mechanisms that prevent antibiotics from achieving the necessary intracellular concentration required to induce cell death [6]. Computational analysis of results revealed that compounds are most likely to accumulate within the cell containing one or more (primary) amino functions, and which are amphiphilic and rigid (low globularity) [8] These accumulation rules do not apply to intrinsically resistant organisms and bacteria with elevated expression of multidrug efflux pumps [8]

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