Mycobacterium tuberculosis Phosphate Uptake System Component PstA2 Is Not Required for Gene Regulation or Virulence

Tischler, Anna D.; Leistikow, Rachel L.; Ramakrishnan, Pavithra; Voskuil, Martin I.; McKinney, John D.

doi:10.1371/journal.pone.0161467

Cited by 14 publications

(17 citation statements)

References 26 publications

(51 reference statements)

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“…The low abundance of pstC2A1 and phoT mutants in biofilms of the Tn-library reveal the importance of phosphorus (Pi) homeostasis in fitness of Mtb cells within biofilm microenvironments. Given that Rv0928-30 encoded PstS3, PstC2, PstA1, and Rv0933 encoded PstB constitute the active Pi-transporter complex (37, 38), a rather mild impairment of Δ pstC2A1 in monoculture biofilms relative to Δ phoT was unexpected. An RNA-seq analysis of the two mutants in comparison with wild-type offers a possible explanation.…”

Section: Resultsmentioning

confidence: 99%

Adaptation of Mycobacterium tuberculosis to biofilm growth is genetically linked to drug tolerance

Richards

Cai

Zill

et al. 2019

Preprint

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21Mycobacterium tuberculosis (Mtb) spontaneously grows at the air-medium interface 22 forming pellicle biofilms, which harbor more drug tolerant persisters than planktonic 23 cultures. The underlying basis for increased persisters in Mtb biofilms is unknown. 24 Using a Tn-seq approach, we show here that multiple genes that are necessary for 25 fitness of Mtb cells within biofilms, but not in planktonic cultures, are also important for 26 their tolerance to a diverse set of stressors and antibiotics. Thus, development of Mtb 27 biofilms appears to be associated with population enrichment, in which endogenous 28 stresses presumably generated by challenging growth conditions within biofilm 29 architecture select for cells that maintain tolerance to exogenous stresses including 30 antibiotic exposure. We further observed that the intrinsic drug tolerance of constituent 31 cells of biofilms determines the frequency of persisters: morphologically 32 indistinguishable monoculture biofilms of a ΔpstC2A1 mutant hypersensitive to 33 rifampicin harbor ~20-fold fewer persisters than wild-type. These findings together allow 34 us to propose that the selection of elite cells during biofilm development significantly 35 contributes to the persister frequency. Furthermore, probing the possibility that the 36 population enrichment is an outcome of unique environment within biofilms, we 37 demonstrate biofilm-specific induction in the synthesis of isonitrile lipopeptides (INLP). 38 Mutation analysis indicates that INLP is necessary for the architecture development of 39 Mtb biofilms. In summary, the study offers an insight into persistence of Mtb biofilms 40 under antibiotic exposure, while identifying INLP as a biomarker for further investigation 41 of this phenomenon. 42 3 SIGNIFICANCE 43 The tuberculosis (TB) pathogen Mycobacterium tuberculosis (Mtb) is one of the 44 deadliest bacterial pathogens known to mankind, and TB treatment is inefficient. A 45 lengthy chemotherapy for TB is attributed to a small subpopulation of Mtb bacilli 46 exhibiting phenotypic tolerance to antibiotics. Drugs targeting these persisters are 47 55 Treatment of tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), entails a 56 multi-drug regimen administered for at least 6 months. A lengthy treatment is 57presumably necessitated by the persistence of a small subpopulation of bacilli, which 58 exhibit phenotypic tolerance to antibiotics (1, 2). Although the mechanism underlying the 59 development of Mtb persisters during infection is unclear, in vitro studies suggest that 60 these bacilli probably develop through both stochastic and induced mechanisms(3-6). 61The persistence of microbes against antibiotics has been closely linked to their 62 ability to grow as sessile, three-dimensionally organized, matrix encapsulated, 63 multicellular communities called biofilms (7-11). Biofilm-related antibiotic tolerance is 64 rendered particularly relevant by the fact that a majority of chronic microbial infections in 65 humans occur as biofi...

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Section: Resultsmentioning

confidence: 99%

Adaptation of Mycobacterium tuberculosis to biofilm growth is genetically linked to drug tolerance

Richards

Cai

Zill

et al. 2019

Preprint

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“…This has led E. coli to become the paradigm for bacterial phosphate homeostasis, a position borne out by virulence studies with many enterobacterial pathogens (8)(9)(10)(11)(12). However, P i acquisition and homeostasis in S. aureus do not follow the rules of E. coli, as is the case for several other organisms, including B. subtilis, S. pneumoniae, M. tuberculosis, and V. cholerae (14,17,19,20,32). The most notable difference is that in addition to PitA and PstSCAB, S. aureus possesses a third functional P i importer, NptA.…”

Section: Discussionmentioning

confidence: 99%

Acquisition of the Phosphate Transporter NptA Enhances Staphylococcus aureus Pathogenesis by Improving Phosphate Uptake in Divergent Environments

et al. 2018

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During infection, pathogens must obtain all inorganic nutrients, such as phosphate, from the host. Despite the essentiality of phosphate for all forms of life, how obtains this nutrient during infection is unknown. Differing from, the paradigm for bacterial phosphate acquisition, which has two inorganic phosphate (P) importers, genomic analysis suggested that possesses three distinct P transporters: PstSCAB, PitA, and NptA. While and are expressed in phosphate-replete media, expression of all three transporters is induced by phosphate limitation. The loss of a single transporter did not affect However, disruption of any two systems significantly reduced P accumulation and growth in divergent environments. These findings indicate that PstSCAB, PitA, and NptA have overlapping but nonredundant functions, thus expanding the environments in which can successfully obtain P Consistent with this idea, in a systemic mouse model of disease, loss of any one transporter did not decrease staphylococcal virulence. However, loss of NptA in conjunction with either PstSCAB or PitA significantly reduced the ability of to cause infection. These observations suggest that P acquisition via NptA is particularly important for the pathogenesis of While our analysis suggests that NptA homologs are widely distributed among bacteria, closely related less pathogenic staphylococcal species do not possess this importer. Altogether, these observations indicate that P uptake by differs from established models and that acquisition of a third transporter enhances the ability of the bacterium to cause infection.

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“…M. tuberculosis encodes two PstSCAB transporters and two PhoU proteins and uses these proteins in an unusual scheme to sense P i . While only one copy of PstSCAB contributes to P i regulation, both PhoU proteins are involved in P i signaling through the mycobacterial PhoPR homologs (38,44,53,59). S. pneumoniae also contains two pst loci, each with its own associated phoU; whereas each PhoU protein regulates the activity of its cognate Pst transporter, only PhoU2 participates in P i signaling by interacting with the pneumococcal PhoPR homologs (20).…”

Section: Discussionmentioning

confidence: 99%

PhoPR Contributes to Staphylococcus aureus Growth during Phosphate Starvation and Pathogenesis in an Environment-Specific Manner

2018

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Microbial pathogens must obtain all essential nutrients, including phosphate, from the host. To optimize phosphate acquisition in diverse and dynamic environments, such as mammalian tissues, many bacteria use the PhoPR two-component system. Despite the necessity of this system for virulence in several species, PhoPR has not been studied in the major human pathogen To illuminate its role in staphylococcal physiology, we initially assessed whether PhoPR controls the expression of the three inorganic phosphate (P) importers (PstSCAB, NptA, and PitA) in This analysis revealed that PhoPR is required for the expression of and and can modulate expression. Consistent with a role in phosphate homeostasis, PhoPR-mediated regulation of the transporters is influenced by phosphate availability. Further investigations revealed that PhoPR is necessary for growth under P-limiting conditions, and in some environments, its primary role is to induce the expression of or Interestingly, in other environments, PhoPR is necessary for growth independent of P transporter expression, indicating that additional PhoPR-regulated factors promote adaptation to low-P conditions. Together, these data suggest that PhoPR differentially contributes to growth in an environment-specific manner. In a systemic infection model, a mutant of lacking PhoPR is highly attenuated. Further investigation revealed that PhoPR-regulated factors, in addition to P transporters, are critical for staphylococcal pathogenesis. Cumulatively, these findings point to an important role for PhoPR in orchestrating P acquisition as well as transporter-independent mechanisms that contribute to virulence.

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Mycobacterium tuberculosis Phosphate Uptake System Component PstA2 Is Not Required for Gene Regulation or Virulence

Cited by 14 publications

References 26 publications

Adaptation of Mycobacterium tuberculosis to biofilm growth is genetically linked to drug tolerance

Adaptation of Mycobacterium tuberculosis to biofilm growth is genetically linked to drug tolerance

Acquisition of the Phosphate Transporter NptA Enhances Staphylococcus aureus Pathogenesis by Improving Phosphate Uptake in Divergent Environments

PhoPR Contributes to Staphylococcus aureus Growth during Phosphate Starvation and Pathogenesis in an Environment-Specific Manner

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