2-Aminobenzothiazoles Inhibit Virulence Gene Expression and Block Polymyxin Resistance inSalmonella enterica

One promising strategy to combat antibiotic-resistant bacteria is to develop compounds that block bacterial defenses against antibacterial conditions produced by the innate immune system.Salmonella enterica, which causes food-borne gastroenteritis and typhoid fever, requires histidine kinases (HKs) to resist innate immune defenses such as cationic antimicrobial peptides (CAMPs). Herein, we report that 2-aminobenzothiazoles block histidine kinase-dependent phenotypes inSalmonella entericaserotype Typhimurium. We found that 2-aminobenzothiazoles inhibited growth under low Mg2+, a stressful condition that requires histidine kinase-mediated responses, and decreased expression of the virulence genespagCandpagK. Furthermore, we discovered that 2-aminobenzothiazoles weakenSalmonella's resistance to polymyxin B and polymyxin E, which are last-line antibiotics and models for host defense CAMPs. These findings raise the possibilities that 2-aminobenzothiazoles can block HK-mediated bacterial defenses and can be used in combination with polymyxins to treat infections caused bySalmonella.