A Two-Component-System-Governed Regulon That Includes a beta-Lactamase Gene is Responsive to Cell Envelope Disturbance

Abstract

beta-Lactamase production facilitates bacterial survival in nature and affects many infection therapies. However, much of its regulation remains unexplored. We used a genetics-based approach to identify a two-component system (TCS) present in a strain of Burkholderia thailandensis essential for the regulated expression of a class A beta-lactamase gene, penL, by sensing subtle envelope disturbance caused by beta-lactams, polymyxin B, or other chemical agents. The genes encoding stress responses and resistance to various antibiotics were coregulated, as were the catabolic genes that enabled the B. thailandensis strain to grow on penicillin G or phenylacetate, a degradation product of penicillin G. This regulon has likely evolved to facilitate bacterial survival in the soil microbiome that contains a multitude of antibiotic producers. Practically, this regulatory system makes this TCS, which we named BesRS, an excellent drug target for the purpose of increasing antibiotic efficacy in combination therapies for Burkholderia infections. IMPORTANCE beta-lactam antibiotics are the most frequently used drugs to treat infectious diseases. Although the production of beta-lactamases by bacteria is the main cause of treatments being compromised, much of the gene regulation mechanism governing the levels of these enzymes has not been fully explored. In this study, we report a novel beta-lactamase gene regulation mechanism that is governed by a two-component system responding to disturbances in the cell envelope. We showed gene regulation is a part of a regulon that includes genes involved in stress responses, resistance to various antibiotics, and a catabolic pathway for beta-lactams. This regulon may have been evolved to facilitate bacterial survival in the soil niches, which are highly competitive environments because of the presence of various antibiotic-producing microbes. The discovery of the beta-lactamase gene regulation mechanism opens new avenues for developing therapeutic strategies in the fight against antibiotic resistance.