Impact of Hypoxia on Drug Resistance and Growth Characteristics of Mycobacterium tuberculosis Clinical Isolates

Z, Liu; Gao, Yulu; Yang, Hua; Bao, Haiyang; Qin, Lianhua; Zhu, Changtai; Chen, Yawen; Hu, Zhongyi

doi:10.1371/journal.pone.0166052

Cited by 12 publications

(8 citation statements)

References 42 publications

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“…Mycobacteria were grown to mid-log phase in 7H9 broth with 10% ADC, 0.05% Tween 80, and antibiotics, as required. Growth curves for each strain were determined using a Bioscreen C Growth Curve Instrument (Labsystems Oy, Helsinki, Finland) and a honeycomb plate with 100 wells (Labsystems Oy) 48 . Briefly, 200 μL of each bacterial suspension, adjusted to a similar density, was added to each well and cultured with shaking at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

Lysine acetylation of DosR regulates the hypoxia response of Mycobacterium tuberculosis

Yang

Wang

et al. 2018

Emerging Microbes & Infections

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Tuberculosis caused by Mycobacterium tuberculosis (Mtb) infection remains a large global public health problem. One striking characteristic of Mtb is its ability to adapt to hypoxia and trigger the ensuing transition to a dormant state for persistent infection, but how the hypoxia response of Mtb is regulated remains largely unknown. Here we performed a quantitative acetylome analysis to compare the acetylation profile of Mtb under aeration and hypoxia, and showed that 377 acetylation sites in 269 Mtb proteins were significantly changed under hypoxia. In particular, deacetylation of dormancy survival regulator (DosR) at K182 promoted the hypoxia response in Mtb and enhanced the transcription of DosR-targeted genes. Mechanistically, recombinant DosRK182R protein demonstrated enhanced DNA-binding activity in comparison with DosRK182Q protein. Moreover, Rv0998 was identified as an acetyltransferase that mediates the acetylation of DosR at K182. Deletion of Rv0998 also promoted the adaptation of Mtb to hypoxia and the transcription of DosR-targeted genes. Mice infected with an Mtb strain containing acetylation-defective DosRK182R had much lower bacterial counts and less severe histopathological impairments compared with those infected with the wild-type strain. Our findings suggest that hypoxia induces the deacetylation of DosR, which in turn increases its DNA-binding ability to promote the transcription of target genes, allowing Mtb to shift to dormancy under hypoxia.

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Section: Methodsmentioning

confidence: 99%

Lysine acetylation of DosR regulates the hypoxia response of Mycobacterium tuberculosis

Yang

Wang

et al. 2018

Emerging Microbes & Infections

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“…The implications of hypoxic condition in caseum are significant because an in vitro model that gradually depletes oxygen and then maintains low oxygen tension (Wayne model) triggers an adaptive dormancy response in M. tuberculosis (65,116). In this model, M. tuberculosis arrests replication, decreases intracellular ATP levels (117), represses an array of cellular functions, including protein and DNA synthesis (118), and develops phenotypic resistance to most TB-active antibiotics (119,120). At the molecular level, the dormancy response to hypoxia is mediated by the transcription factor Rv3133c, or DosR (for dormancy survival regulator) (87,118,121).…”

Section: Hypoxiamentioning

confidence: 99%

Caseum: a Niche for Mycobacterium tuberculosis Drug-Tolerant Persisters

Sarathy

Dartois

2020

Clin Microbiol Rev

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SUMMARY Caseum, the central necrotic material of tuberculous lesions, is a reservoir of drug-recalcitrant persisting mycobacteria. Caseum is found in closed nodules and in open cavities connecting with an airway. Several commonly accepted characteristics of caseum were established during the preantibiotic era, when autopsies of deceased tuberculosis (TB) patients were common but methodologies were limited. These pioneering studies generated concepts such as acidic pH, low oxygen tension, and paucity of nutrients being the drivers of nonreplication and persistence in caseum. Here we review widely accepted beliefs about the caseum-specific stress factors thought to trigger the shift of Mycobacterium tuberculosis to drug tolerance. Our current state of knowledge reveals that M. tuberculosis is faced with a lipid-rich diet rather than nutrient deprivation in caseum. Variable caseum pH is seen across lesions, possibly transiently acidic in young lesions but overall near neutral in most mature lesions. Oxygen tension is low in the avascular caseum of closed nodules and high at the cavity surface, and a gradient of decreasing oxygen tension likely forms toward the cavity wall. Since caseum is largely made of infected and necrotized macrophages filled with lipid droplets, the microenvironmental conditions encountered by M. tuberculosis in foamy macrophages and in caseum bear many similarities. While there remain a few knowledge gaps, these findings constitute a solid starting point to develop high-throughput drug discovery assays that combine the right balance of oxygen tension, pH, lipid abundance, and lipid species to model the profound drug tolerance of M. tuberculosis in caseum.

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“…The transporter Rv0194 has two TMDs and two NBDs encoded by a single gene (Table 3). Disruption of the rv0194 gene promotes the in vitro growth of H37Rv [46], although proteomics studies have shown that it is a non-essential gene [47,125]. On the other hand, rv0194 is significantly upregulated under hypoxic conditions compared to under aerobic conditions [126].…”

Section: Drug Efflux and Resistance In M Tuberculosismentioning

confidence: 99%

The ATP-Binding Cassette (ABC) Transport Systems in Mycobacterium tuberculosis: Structure, Function, and Possible Targets for Therapeutics

Oliveira

Balan

2020

Biology

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Mycobacterium tuberculosis is the etiological agent of tuberculosis (TB), a disease that affects millions of people in the world and that is associated with several human diseases. The bacillus is highly adapted to infect and survive inside the host, mainly because of its cellular envelope plasticity, which can be modulated to adapt to an unfriendly host environment; to manipulate the host immune response; and to resist therapeutic treatment, increasing in this way the drug resistance of TB. The superfamily of ATP-Binding Cassette (ABC) transporters are integral membrane proteins that include both importers and exporters. Both types share a similar structural organization, yet only importers have a periplasmic substrate-binding domain, which is essential for substrate uptake and transport. ABC transporter-type importers play an important role in the bacillus physiology through the transport of several substrates that will interfere with nutrition, pathogenesis, and virulence. Equally relevant, exporters have been involved in cell detoxification, nutrient recycling, and antibiotics and drug efflux, largely affecting the survival and development of multiple drug-resistant strains. Here, we review known ABC transporters from M. tuberculosis, with particular focus on the diversity of their structural features and relevance in infection and drug resistance.

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Impact of Hypoxia on Drug Resistance and Growth Characteristics of Mycobacterium tuberculosis Clinical Isolates

Cited by 12 publications

References 42 publications

Lysine acetylation of DosR regulates the hypoxia response of Mycobacterium tuberculosis

Lysine acetylation of DosR regulates the hypoxia response of Mycobacterium tuberculosis

Caseum: a Niche for Mycobacterium tuberculosis Drug-Tolerant Persisters

The ATP-Binding Cassette (ABC) Transport Systems in Mycobacterium tuberculosis: Structure, Function, and Possible Targets for Therapeutics

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