Abstract
BackgroundTwo-component systems have emerged as compelling targets for antibacterial drug design for a number of reasons including the distinct histidine phosphorylation property of their constituent sensor kinases. The DevR-DevS/DosT two component system of Mycobacterium tuberculosis (M. tb) is essential for survival under hypoxia, a stress associated with dormancy development in vivo. In the present study a combinatorial peptide phage display library was screened for DevS histidine kinase interacting peptides with the aim of isolating inhibitors of DevR-DevS signaling.ResultsDevS binding peptides were identified from a phage display library after three rounds of panning using DevS as bait. The peptides showed sequence similarity with conserved residues in the N-terminal domain of DevR and suggested that they may represent interacting surfaces between DevS and DevR. Two DevR mimetic peptides were found to specifically inhibit DevR-dependent transcriptional activity and restrict the hypoxic survival of M. tb. The mechanism of peptide action is majorly attributed to an inhibition of DevS autokinase activity.ConclusionsThese findings demonstrate that DevR mimetic peptides impede DevS activation and that intercepting DevS activation at an early step in the signaling cascade impairs M. tb survival in a hypoxia persistence model.
Highlights
Two-component systems have emerged as compelling targets for antibacterial drug design for a number of reasons including the distinct histidine phosphorylation property of their constituent sensor kinases
Two component systems are considered as compelling targets for drug design due to a number of reasons including their absence in higher eukaryotes, the difference in bacterial two-component signaling as compared to signaling pathways in eukaryotes, and most importantly, the essential roles they play in bacterial viability, virulence and drug resistance
In conclusion, the observed peptide-mediated inhibition, albeit at millimolar concentrations, demonstrates that interference of DevS/DosT signaling at the step of autokinase activity severely attenuates M. tb adaptation and survival under hypoxia, a condition that prevails within granulomas and is a likely trigger for bacterial dormancy initiation and maintenance in vivo during latent TB
Summary
Two-component systems have emerged as compelling targets for antibacterial drug design for a number of reasons including the distinct histidine phosphorylation property of their constituent sensor kinases. The DevR dormancy regulon of Mycobacterium tuberculosis (M. tb) is a transcriptional program induced by low oxygen tension, nitric oxide (NO), carbon monoxide (CO) or vitamin C treatment that enables bacterial adaptation and survival during periods of non-replicating persistence in in vitro models of dormancy [1,2,3,4]. This regulon is believed to assist bacterial survival during latent tuberculosis (TB) infection, a chronic asymptomatic state that afflicts one-third of the global population [5]. A recent study identified potential PhoQ inhibitor compounds that inhibited autophosphorylation and inhibited severe keratoconjunctival inflammation in mice inoculated with Shigella flexneri [14], suggesting that two-component systems are potential targets for the development of drugs against bacteria
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