Lacticaseicin 30 and Colistin as a Promising Antibiotic Formulation against Gram-Negative β-Lactamase-Producing Strains and Colistin-Resistant Strains.

Désiré Madi-Moussa,Djamel Drider,Yanath Belguesmia,Audrey Charlet,Françoise Coucheney

doi:10.3390/antibiotics11010020

Abstract

Antimicrobial resistance is a global health concern across the world and it is foreseen to swell if no actions are taken now. To help curbing this well announced crisis different strategies are announced, and these include the use of antimicrobial peptides (AMP), which are remarkable molecules known for their killing activities towards pathogenic bacteria. Bacteriocins are ribosomally synthesized AMP produced by almost all prokaryotic lineages. Bacteriocins, unlike antibiotics, offer a set of advantages in terms of cytotoxicity towards eukaryotic cells, their mode of action, cross-resistance and impact of microbiota content. Most known bacteriocins are produced by Gram-positive bacteria, and specifically by lactic acid bacteria (LAB). LAB-bacteriocins were steadily reported and characterized for their activity against genetically related Gram-positive bacteria, and seldom against Gram-negative bacteria. The aim of this study is to show that lacticaseicin 30, which is one of the bacteriocins produced by Lacticaseibacillus paracasei CNCM I-5369, is active against Gram-negative clinical strains (Salmonella enterica Enteritidis H10, S. enterica Typhimurium H97, Enterobacter cloacae H51, Escherichia coli H45, E. coli H51, E. coli H66, Klebsiella oxytoca H40, K. pneumoniae H71, K. variicola H77, K. pneumoniae H79, K. pneumoniae H79), whereas antibiotics failed. In addition, lacticaseicin 30 and colistin enabled synergistic interactions towards the aforementioned target Gram-negative clinical strains. Further, the combinations of lacticaseicin 30 and colistin prompted a drastic downregulation of mcr-1 and mcr-9 genes, which are associated with the colistin resistance phenotypes of these clinical strains. This report shows that lacticaseicin 30 is active against Gram-negative clinical strains carrying a rainbow of mcr genes, and the combination of these antimicrobials constitutes a promising therapeutic option that needs to be further exploited.

Highlights

Antimicrobial resistance (AMR), which has existed long before the antimicrobial era, is recognized as a serious public health threat around the world
The antibiotics tested here are those recommended by European Committee on Antimicrobial Susceptibility Testing (EUCAST) for Enterobacterales and the breakpoints used to assess their sensitivity, resistance or intermediate phenotype are from the EUCAST
The results using MAST disks indicate that these strains exhibited clearly an extended spectrum beta-lactamase (ESBL) phenotype, associated with AmpC for the H77 and H51 strains, which seems to be inducible for this last one (Table 1)

Summary

Introduction

Antimicrobial resistance (AMR), which has existed long before the antimicrobial era, is recognized as a serious public health threat around the world. Antibiotics started to fail because of their overuse and misuse in human and animal medicine, as well as for their inappropriate recommendation Unsuspected contributors such as commensal organisms, which are interconnected with microbial communities, are thought to play a role in the spread of this resistance [3]. The global effort to develop new antibiotics or modify the existing ones in order to fight AMR is considered overall to be a huge task. In spite of this worrying situation, large pharmaceutical companies have dropped out the market of antibiotics, in favor of advantageous lines of drug development such as those utilized in the cancer treatments [4,5], arguing that the cost–benefit ratio is much more favorable for other drugs

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