Essential Two-Component Systems Regulating Cell Envelope Functions: Opportunities for Novel Antibiotic Therapies
Two-component regulatory systems (2CRSs) are widely used by bacteria to sense and respond to environmental stimuli with coordinated changes in gene expression. Systems are normally comprised of a sensory kinase protein that activates a transcriptional regulator by phosphorylation. Mycobacteria have few 2CRSs, but they are of key importance for bacterial survival and play important roles in pathogenicity. Mycobacterium tuberculosis has 12 paired two-component regulatory systems (which include a system with two regulators and one sensor, and a split sensor system), as well as four orphan regulators. Several systems are involved in virulence, and disruption of different systems leads to attenuation or hypervirulence. PhoPR plays a major role in regulating cell wall composition, and its inactivation results in sufficient attenuation of M. tuberculosis that deletion strains are live vaccine candidates. MprAB controls the stress response and is required for persistent infections. SenX3-RegX3 is required for control of aerobic respiration and phosphate uptake, and PrrAB is required for adaptation to intracellular infection. MtrAB is an essential system that controls DNA replication and cell division. The remaining systems (KdpDE, NarL, TrcRS, TcrXY, TcrA, PdtaRS, and four orphan regulators) are less well understood. The structure and binding motifs for several regulators have been characterized, revealing variations in function and operation. The sensors are less well characterized, and stimuli for many remain to be confirmed. This chapter reviews our current understanding of the role of two-component systems in mycobacteria, in particular M. tuberculosis.