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 5 publications

(2 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.

View full text Add to dashboard Cite

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Functionalized tin-loaded mesoporous silica nanoparticles for targeted therapy of triple-negative breast cancer: Evaluation of cytogenetic toxicity

Choudante,

Mamilla,

Kongari

et al. 2024

Journal of Drug Delivery Science and Technology

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Increased Susceptibility of Mycobacterium tuberculosis to Ethionamide by Expressing PPs-Induced Rv0560c

et al. 2022

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Tuberculosis, an infectious disease, is one of the leading causes of death worldwide. Drug-resistant tuberculosis exacerbates its threat. Despite long-term and costly treatment with second-line drugs, treatment failure rates and mortality remain high. Therefore, new strategies for developing new drugs and improving the efficiency of existing drug treatments are urgently needed. Our research team reported that PPs, a new class of potential anti-tuberculosis drug candidates, can inhibit the growth of drug-resistant Mycobacterium tuberculosis. Here, we report a synergistic effect of PPs with ethionamide (ETH), one of the second-line drugs, as a result of further research on PPs. While investigating gene expression changes based on microarray and 2DE (two-dimensional gel electrophoresis), it was found that PPs induced the greatest overexpression of Rv0560c in M. tuberculosis. Based on this result, a protein microarray using Rv0560c protein was performed, and it was confirmed that Rv0560c had the highest interaction with EthR, a repressor for EthA involved in activating ETH. Accordingly, a synergistic experiment was conducted under the hypothesis of increased susceptibility of ETH to M. tuberculosis by PPs. As a result, in the presence of 0.5× MIC PPs, ETH showed a growth inhibitory effect on drug-sensitive and -resistant M. tuberculosis even at a much lower concentration of about 10-fold than the original MIC of ETH. It is also suggested that the effect was due to the interaction between PPs and Rv2887, the repressor of Rv0560c. This effect was also confirmed in a mouse model of pulmonary tuberculosis, confirming the potential of PPs as a booster to enhance the susceptibility of M. tuberculosis to ETH in treating drug-resistant tuberculosis. However, more in-depth mechanistic studies and extensive animal and clinical trials are needed in the future.

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

Cited by 5 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

Functionalized tin-loaded mesoporous silica nanoparticles for targeted therapy of triple-negative breast cancer: Evaluation of cytogenetic toxicity

Increased Susceptibility of Mycobacterium tuberculosis to Ethionamide by Expressing PPs-Induced Rv0560c

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