Targeting redox heterogeneity to counteract drug tolerance in replicating Mycobacterium tuberculosis.
Identifieur interne : 000C05 ( Ncbi/Checkpoint ); précédent : 000C04; suivant : 000C06Targeting redox heterogeneity to counteract drug tolerance in replicating Mycobacterium tuberculosis.
Auteurs : Richa Mishra [Inde] ; Sakshi Kohli [Inde] ; Nitish Malhotra [Inde] ; Parijat Bandyopadhyay [Inde] ; Mansi Mehta [Inde] ; Mohamedhusen Munshi [Inde] ; Vasista Adiga [Inde] ; Vijay Kamal Ahuja [Inde] ; Radha K. Shandil [Inde] ; Raju S. Rajmani [Inde] ; Aswin Sai Narain Seshasayee [Inde] ; Amit Singh [Inde]Source :
- Science translational medicine [ 1946-6242 ] ; 2019.
Abstract
The capacity of Mycobacterium tuberculosis (Mtb) to tolerate multiple antibiotics represents a major problem in tuberculosis (TB) management. Heterogeneity in Mtb populations is one of the factors that drives antibiotic tolerance during infection. However, the mechanisms underpinning this variation in bacterial population remain poorly understood. Here, we show that phagosomal acidification alters the redox physiology of Mtb to generate a population of replicating bacteria that display drug tolerance during infection. RNA sequencing of this redox-altered population revealed the involvement of iron-sulfur (Fe-S) cluster biogenesis, hydrogen sulfide (H2S) gas, and drug efflux pumps in antibiotic tolerance. The fraction of the pH- and redox-dependent tolerant population increased when Mtb infected macrophages with actively replicating HIV-1, suggesting that redox heterogeneity could contribute to high rates of TB therapy failure during HIV-TB coinfection. Pharmacological inhibition of phagosomal acidification by the antimalarial drug chloroquine (CQ) eradicated drug-tolerant Mtb, ameliorated lung pathology, and reduced postchemotherapeutic relapse in in vivo models. The pharmacological profile of CQ (Cmax and AUClast) exhibited no major drug-drug interaction when coadministered with first line anti-TB drugs in mice. Our data establish a link between phagosomal pH, redox metabolism, and drug tolerance in replicating Mtb and suggest repositioning of CQ to shorten TB therapy and achieve a relapse-free cure.
DOI: 10.1126/scitranslmed.aaw6635
PubMed: 31723039
Affiliations:
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<front><div type="abstract" xml:lang="en">The capacity of <i>Mycobacterium tuberculosis</i>
(<i>Mtb</i>
) to tolerate multiple antibiotics represents a major problem in tuberculosis (TB) management. Heterogeneity in <i>Mtb</i>
populations is one of the factors that drives antibiotic tolerance during infection. However, the mechanisms underpinning this variation in bacterial population remain poorly understood. Here, we show that phagosomal acidification alters the redox physiology of <i>Mtb</i>
to generate a population of replicating bacteria that display drug tolerance during infection. RNA sequencing of this redox-altered population revealed the involvement of iron-sulfur (Fe-S) cluster biogenesis, hydrogen sulfide (H<sub>2</sub>
S) gas, and drug efflux pumps in antibiotic tolerance. The fraction of the pH- and redox-dependent tolerant population increased when <i>Mtb</i>
infected macrophages with actively replicating HIV-1, suggesting that redox heterogeneity could contribute to high rates of TB therapy failure during HIV-TB coinfection. Pharmacological inhibition of phagosomal acidification by the antimalarial drug chloroquine (CQ) eradicated drug-tolerant <i>Mtb</i>
, ameliorated lung pathology, and reduced postchemotherapeutic relapse in in vivo models. The pharmacological profile of CQ (<i>C</i>
<sub>max</sub>
and AUC<sub>last</sub>
) exhibited no major drug-drug interaction when coadministered with first line anti-TB drugs in mice. Our data establish a link between phagosomal pH, redox metabolism, and drug tolerance in replicating <i>Mtb</i>
and suggest repositioning of CQ to shorten TB therapy and achieve a relapse-free cure.</div>
</front>
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<affiliations><list><country><li>Inde</li>
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<name sortKey="Adiga, Vasista" sort="Adiga, Vasista" uniqKey="Adiga V" first="Vasista" last="Adiga">Vasista Adiga</name>
<name sortKey="Ahuja, Vijay Kamal" sort="Ahuja, Vijay Kamal" uniqKey="Ahuja V" first="Vijay Kamal" last="Ahuja">Vijay Kamal Ahuja</name>
<name sortKey="Bandyopadhyay, Parijat" sort="Bandyopadhyay, Parijat" uniqKey="Bandyopadhyay P" first="Parijat" last="Bandyopadhyay">Parijat Bandyopadhyay</name>
<name sortKey="Kohli, Sakshi" sort="Kohli, Sakshi" uniqKey="Kohli S" first="Sakshi" last="Kohli">Sakshi Kohli</name>
<name sortKey="Malhotra, Nitish" sort="Malhotra, Nitish" uniqKey="Malhotra N" first="Nitish" last="Malhotra">Nitish Malhotra</name>
<name sortKey="Mehta, Mansi" sort="Mehta, Mansi" uniqKey="Mehta M" first="Mansi" last="Mehta">Mansi Mehta</name>
<name sortKey="Munshi, Mohamedhusen" sort="Munshi, Mohamedhusen" uniqKey="Munshi M" first="Mohamedhusen" last="Munshi">Mohamedhusen Munshi</name>
<name sortKey="Rajmani, Raju S" sort="Rajmani, Raju S" uniqKey="Rajmani R" first="Raju S" last="Rajmani">Raju S. Rajmani</name>
<name sortKey="Seshasayee, Aswin Sai Narain" sort="Seshasayee, Aswin Sai Narain" uniqKey="Seshasayee A" first="Aswin Sai Narain" last="Seshasayee">Aswin Sai Narain Seshasayee</name>
<name sortKey="Shandil, Radha K" sort="Shandil, Radha K" uniqKey="Shandil R" first="Radha K" last="Shandil">Radha K. Shandil</name>
<name sortKey="Singh, Amit" sort="Singh, Amit" uniqKey="Singh A" first="Amit" last="Singh">Amit Singh</name>
</country>
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