Essential Two-Component Systems Regulating Cell Envelope Functions: Opportunities for Novel Antibiotic Therapies

Novel therapies are urgently needed to alleviate the current crisis of multiple drug-resistant infections. The bacterial signal transduction mechanisms, known as two-component systems (TCSs), are ideal targets of novel inhibitory molecules. Highly restricted to the bacterial world, TCSs control a diverse set of cellular functions, namely virulence, response to cell envelope stress, and drug efflux. Impaired regulation of any of these aspects could affect the susceptibility of bacterial pathogens to antibiotics, which highlights the potential of TCS as targets of antibiotic adjuvant therapies. Moreover, new high-density transposon mutagenesis methods have revealed the existence of TCSs required for growth and viability. Experimental validation of gene essentiality and phenotypic characterization of knockdown mutants indicate that essential TCSs regulate aspects of the cell envelope homeostasis in coordination with cell division. In this review, we describe essential TCSs, and their potentials as targets for antibacterial molecules. We also discuss methods for the identification of small molecules that inhibit TCSs and possible reasons why antibacterial molecules targeting essential TCSs have not yet reached clinical trials.