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

β-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 β-lactamase gene, penL, by sensing subtle envelope disturbance caused by β-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.