title: Polyphosphate deficiency in Mycobacterium tuberculosis is associated with enhanced drug susceptibility and impaired growth in guinea pigs.
abstract: Inorganic polyphosphate (polyP), a linear polymer of hundreds of phosphate residues linked by ATP-like phosphoanhydride bonds, is found in all organisms and performs a wide variety of functions. This study shows that polyP accumulation occurs in Mycobacterium tuberculosis upon exposure to various stress conditions. M. tuberculosis possesses a single homolog of ppk-1, and we have disrupted ppk-1 in the M. tuberculosis genome by allelic replacement. The mutant strain exhibited negligible levels of intracellular polyP, decreased expression of sigF and phoP, and reduced growth in the stationary phase and displayed a survival defect in response to nitrosative stress and in THP-1 macrophages compared to the wild-type strain. We report that reduction in polyP levels is associated with increased susceptibility of M. tuberculosis to certain TB drugs and impairs its ability to cause disease in guinea pigs. These results suggest that polyP contributes to persistence of M. tuberculosis in vitro and plays an important role in the physiology of bacteria residing within guinea pigs.
authors.affiliation: Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, Haryana, India. ramandeep@thsti.res.in
authors.forename: Ramandeep
authors.initials: R
authors.lastname: Singh
authors.forename: Mamta
authors.initials: M
authors.lastname: Singh
authors.forename: Garima
authors.initials: G
authors.lastname: Arora
authors.forename: Santosh
authors.initials: S
authors.lastname: Kumar
authors.forename: Prabhakar
authors.initials: P
authors.lastname: Tiwari
authors.forename: Saqib
authors.initials: S
authors.lastname: Kidwai
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D006168:Guinea Pigs; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism* / Q000472:pathogenicity*; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism; D011122:Polyphosphates / Q000378:metabolism*; D013312:Stress, Physiological; D014376:Tuberculosis / Q000382:microbiology / Q000473:pathology; D014774:Virulence
chemical_list: D000995:Antitubercular Agents; D011122:Polyphosphates; D010770:Phosphotransferases