Antibiotic Production and Antibiotic Resistance: The Two Sides of AbrB1/B2, a Two-Component System of Streptomyces coelicolor.

Juan F Alzate,Ricardo Sánchez De La Nieta,Sergio Antoraz,Ramón I Santamaría,Margarita Díaz

doi:10.3389/fmicb.2020.587750

Abstract

Antibiotic resistance currently presents one of the biggest threats to humans. The development and implementation of strategies against the spread of superbugs is a priority for public health. In addition to raising social awareness, approaches such as the discovery of new antibiotic molecules and the elucidation of resistance mechanisms are common measures. Accordingly, the two-component system (TCS) of Streptomyces coelicolor AbrB1/B2, offer amenable ways to study both antibiotic production and resistance. Global transcriptomic comparisons between the wild-type strain S. coelicolor M145 and the mutant ΔabrB, using RNA-Seq, showed that the AbrB1/B2 TCS is implicated in the regulation of different biological processes associated with stress responses, primary and secondary metabolism, and development and differentiation. The ΔabrB mutant showed the up-regulation of antibiotic biosynthetic gene clusters and the down-regulation of the vancomycin resistance gene cluster, according to the phenotypic observations of increased antibiotic production of actinorhodin and undecylprodigiosin, and greater susceptibility to vancomycin. The role of AbrB1/B2 in vancomycin resistance has also been shown by an in silico analysis, which strongly indicates that AbrB1/B2 is a homolog of VraR/S from Staphylococcus aureus and LiaR/S from Enterococcus faecium/Enterococcus faecalis, both of which are implied in vancomycin resistance in these pathogenic organisms that present a serious threat to public health. The results obtained are interesting from a biotechnological perspective since, on one hand, this TCS is a negative regulator of antibiotic production and its high degree of conservation throughout Streptomyces spp. makes it a valuable tool for improving antibiotic production and the discovery of cryptic metabolites with antibiotic action. On the other hand, AbrB1/B2 contributes to vancomycin resistance and is a homolog of VraR/S and LiaR/S, important regulators in clinically relevant antibiotic-resistant bacteria. Therefore, the study of AbrB1/B2 could provide new insight into the mechanism of this type of resistance.

Highlights

The emergence and spread of antibiotic resistant bacteria currently present great challenges to humans as highlighted by the World Health Organization (WHO) and the American and European Centers for Disease Control and Prevention, CDC and ECDC, respectively
AbrB1/B2 Is a Canonical Two-Component System Highly Conserved in Streptomycetes
This two-component system (TCS) is present with a high degree of amino acid sequence identity to a wide range of Streptomyces species: Streptomyces griseus, Streptomyces scabiei, Streptomyces venezuelae, Streptomyces avermitilis, Streptomyces albus, and Streptomyces hygroscopicus among others (Supplementary Figure 4)

Summary

Introduction

The emergence and spread of antibiotic resistant bacteria currently present great challenges to humans as highlighted by the World Health Organization (WHO) and the American and European Centers for Disease Control and Prevention, CDC and ECDC, respectively. The ubiquitous genus Streptomyces, with more than 600 species and several sequenced genomes, has a great capacity to produce secondary metabolites with a myriad of antimicrobial, antitumoral, and antifungal activities Many of these metabolites are considered cryptic, owing to the lack of or the reduced ability to be produced in laboratory conditions (Hwang et al, 2014; Barka et al, 2016; Gómez-Escribano et al, 2016; Blaskovich et al, 2017; van der Meij et al, 2017; van der Heul et al, 2018; Mouncey et al, 2019)

Methods

Results

Conclusion