AI Article Synopsis

  • - Mtb (Mycobacterium tuberculosis) uses a protein called HupB to fend off host defenses and antibiotics, crucial for its survival against various stressors like acidic conditions and nutrient scarcity.
  • - HupB is essential for Mtb's resistance to antibiotics like rifampicin and isoniazid; without it, the bacteria become highly vulnerable to these treatments, while its overexpression increases survival rates under stress.
  • - Targeting HupB with a small molecule inhibitor improves Mtb's susceptibility to antibiotics, suggesting that HupB could be a valuable target for developing more effective tuberculosis therapies with lower doses of existing drugs.

Article Abstract

To survive and establish its niche, (Mtb) engages in a steady battle against an array of host defenses and a barrage of antibiotics. Here, we demonstrate that Mtb employs HupB, a nucleoid-associated protein (NAP) as its key player to simultaneously battle and survive in these two stress-inducing fronts. Typically, NAPs are key to bacterial survival under a wide array of environmental or host-mediated stresses. Here, we report that for Mtb to survive under different macrophage-induced assaults including acidic pH, nutrient depletion, oxidative and nitrosative stresses, HupB presence is critical. As expected, the knockout mutant is highly sensitive to these host-mediated stresses. Furthermore, Mtb aptly modulates HupB protein levels to overcome these stresses. We also report that HupB aids Mtb to gain tolerance to high levels of rifampicin (RIF) and isoniazid (INH) exposure. Loss of makes Mtb highly susceptible to even short exposures to reduced amounts of RIF and INH. Overexpressing in Mtb or complementing in the knockout mutant triggers enhanced survival of Mtb under these stresses. We also find that upon loss of , Mtb significantly enhances the permeability of its cell wall by modulating the levels of several surface lipids including phthiocerol dimycocerosates (PDIMs), thus possibly influencing overall susceptibility to host-mediated stresses. Loss of also downregulates efflux pump expression possibly influencing increased susceptibility to INH and RIF. Finally, we find that therapeutic targeting of HupB with SD1, a known small molecule inhibitor, significantly enhances Mtb susceptibility to INH and THP-1 macrophages and significantly reduces MIC to INH. Thus, our data strongly indicate that HupB is a highly promising therapeutic target especially for potential combinatorial shortened therapy with reduced INH and RIF doses.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9441915PMC
http://dx.doi.org/10.3389/fmicb.2022.937970DOI Listing

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