A novel class of antimicrobial drugs selectively targets a Mycobacterium tuberculosis PE-PGRS protein

Seo, Hoonhee; Kim, Sukyung; Mahmud, Hafij Al; Islam, Imtiazul; Yoon, Youjin; Cho, Hyun-Deuk; Nam, Kwanghee; Choi, Jiwon; Gil, Young Sig; Lee, Byung-Eui; Song, Ho‐Yeon

doi:10.1371/journal.pbio.3001648

Cited by 6 publications

(4 citation statements)

References 41 publications

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“…monocytogenes and S. aureus bacteria. , Overall, the bone-adhesive hydrogel did not impair the antibacterial activity of the drug, suggesting that the bone-adhesive hydrogel can improve the antimicrobial effect of the drugs …”

Section: Resultsmentioning

confidence: 87%

“…40,41 Overall, the bone-adhesive hydrogel did not impair the antibacterial activity of the drug, suggesting that the bone-adhesive hydrogel can improve the antimicrobial effect of the drugs. 42 Antitubercular Effects. The bone-adhesive hydrogelloaded MTIT and TMTIPA in vitro antitubercular effects were analyzed (Table S5).…”

Section: Effect Of Inhibitors On M Tuberculosismentioning

confidence: 99%

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Bone-Adhesive Hydrogel for Effective Inhibition of M. tuberculosis and Osteoblast Regeneration

Mehnath,

Sathish Kumar,

Chitra

et al. 2023

ACS Infect. Dis.

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Currently, bone tuberculosis (TB) treatment largely involves lifelong drug prescriptions and surgical intervention, resulting in poor quality of life for patients. Therefore, the fabrication of injectable scaffolds to form a solid framework around the defective bone region is gaining importance over the extensive use of antimicrobial inhibitors. Herein, we synthesized a novel bone-adhesive and thermoresponsive hydrogel via conjugation of poly(N-isopropylacrylamide-co-glycidyl methacrylate) (PNIPAM-co-GMA) and cysteine (CYS). Thiolation of the polymer enables chemical cross-linking with the bone glycoprotein, enhancing bone adhesion and permitting control of scaffold retention time. The PNIPAM-co-GMA-CYS hydrogel shows higher cross-linking behavior at 37 °C, forms a strong gel in 260 s, and has 151 kPa adhesion strength on cortical bone. The lead compounds 5-methyl-5H-[1,2,4]triazino[5,6-b]indole-3-thiol (MTIT) and N-tert-butyl-4-methyl-6-(5-methyl-5H-[1,2,4]triazino[5,6-b]indol-3-ylthio)pyrimidin-2-amine (TMTIPA) were identified by a high-throughput screening method. Effective MTIT and TMTIPA are encapsulated in bone-adhesive hydrogel separately, and both have a high release rate above >70% in 180 h. The MTIT- and TMTIPA-loaded PNIPAM-co-GMA-CYS showed an excellent bactericidal effect, reducing the relative intracellular bacterial survival in macrophages. Furthermore, the as-synthesized hydrogel has outstanding mechanical and biocompatibility properties to become a bone-replacing material and provide support to promote bone repair. This work presents a novel bone-adhesive PNIPAM-co-GMA-CYS for the sustained release of lead compounds toward promising alternative bone TB treatment.

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Section: Resultsmentioning

confidence: 87%

Section: Effect Of Inhibitors On M Tuberculosismentioning

confidence: 99%

Bone-Adhesive Hydrogel for Effective Inhibition of M. tuberculosis and Osteoblast Regeneration

Mehnath,

Sathish Kumar,

Chitra

et al. 2023

ACS Infect. Dis.

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“…Interestingly, a recent study identified mutations within PE_PGRS57 in Mtb that are associated with resistance to a novel anti-tubercular compound [39]. However, since this protein is not essential for Mtb in vitro, it could be that this compound has an additional target [40,41].…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of Mycobacterium marinum ESX-5 Secretion by Novel 1,2,4-oxadiazoles

Rong

Habjan

et al. 2023

Biomolecules

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The ESX-5 secretion system is essential for the viability and virulence of slow-growing pathogenic mycobacterial species. In this study, we identified a 1,2,4-oxadiazole derivative as a putative effector of the ESX-5 secretion system. We confirmed that this 1,2,4-oxadiazole and several newly synthesized derivatives inhibited the ESX-5-dependent secretion of active lipase LipY by Mycobacterium marinum (M. marinum). Despite reduced lipase activity, we did not observe a defect in LipY secretion itself. Moreover, we found that several other ESX-5 substrates, especially the high molecular-weight PE_PGRS MMAR_5294, were even more abundantly secreted by M. marinum treated with several 1,2,4-oxadiazoles. Analysis of M. marinum grown in the presence of different oxadiazole derivatives revealed that the secretion of LipY and the induction of PE_PGRS secretion were, in fact, two independent phenotypes, as we were able to identify structural features in the compounds that specifically induced only one of these phenotypes. Whereas the three most potent 1,2,4-oxadiazoles displayed only a mild effect on the growth of M. marinum or M. tuberculosis in culture, these compounds significantly reduced bacterial burden in M. marinum-infected zebrafish models. In conclusion, we report a 1,2,4-oxadiazole scaffold that dysregulates ESX-5 protein secretion.

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“…A study of Mycobacterium tuberculosis susceptible to the three-drug combination identified a gene (PE-PGR557) not present in members of the microbiome. Thus, there was no change in the bacterial content of gut bacteria [68].…”

Section: Co-infection With Mycobacterium Tuberculosis and Covid-19 In...mentioning

confidence: 91%

Gated Calcium Ion Channel and Mutation Mechanisms in Multidrug-Resistant Tuberculosis

D’Elia

Weinrauch

2023

IJMS

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A wide spectrum of Gram-positive/Gram-negative bacteria has been found resistant to a wide spectrum of antibiotics in the United States of America during the past decade. Drug-resistant tuberculosis is not yet a major threat in North/South America, Europe, and the Middle East. However, the migration of populations in times of drought, famine, and hostilities may increase the global reach of this ancient pathogen. Given an increased spread from China and India to African countries, drug-resistant Mycobacterium tuberculosis has become an emerging topic of concern for Europe and North America. Due to the dangers associated with the spread of pathogens among different populations, the World Health Organization continues to expand healthcare advisories for therapeutic approaches for both stationary and migrating populations. As much of the literature focuses on endemic to pandemic viruses, we remain concerned that other treatable communicable diseases may be ignored. One such disease is multidrug-resistant tuberculosis. We focus on molecular mechanisms that this pathogen relies upon for the development of multidrug resistance via gene mutation and the evolutionary development of new enzyme and calcium channels.

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A novel class of antimicrobial drugs selectively targets a Mycobacterium tuberculosis PE-PGRS protein

Cited by 6 publications

References 41 publications

Bone-Adhesive Hydrogel for Effective Inhibition of M. tuberculosis and Osteoblast Regeneration

Bone-Adhesive Hydrogel for Effective Inhibition of M. tuberculosis and Osteoblast Regeneration

Dysregulation of Mycobacterium marinum ESX-5 Secretion by Novel 1,2,4-oxadiazoles

Gated Calcium Ion Channel and Mutation Mechanisms in Multidrug-Resistant Tuberculosis

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