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1.
Nat Commun ; 15(1): 2005, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38443338

RESUMO

Antimicrobial resistance is a global health threat that requires the development of new treatment concepts. These should not only overcome existing resistance but be designed to slow down the emergence of new resistance mechanisms. Targeted protein degradation, whereby a drug redirects cellular proteolytic machinery towards degrading a specific target, is an emerging concept in drug discovery. We are extending this concept by developing proteolysis targeting chimeras active in bacteria (BacPROTACs) that bind to ClpC1, a component of the mycobacterial protein degradation machinery. The anti-Mycobacterium tuberculosis (Mtb) BacPROTACs are derived from cyclomarins which, when dimerized, generate compounds that recruit and degrade ClpC1. The resulting Homo-BacPROTACs reduce levels of endogenous ClpC1 in Mycobacterium smegmatis and display minimum inhibitory concentrations in the low micro- to nanomolar range in mycobacterial strains, including multiple drug-resistant Mtb isolates. The compounds also kill Mtb residing in macrophages. Thus, Homo-BacPROTACs that degrade ClpC1 represent a different strategy for targeting Mtb and overcoming drug resistance.


Assuntos
Mycobacterium smegmatis , Mycobacterium tuberculosis , Proteólise , Dimerização , Descoberta de Drogas
2.
Antimicrob Agents Chemother ; 66(12): e0056422, 2022 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-36445129

RESUMO

Mycobacterial pathogens, including nontuberculous mycobacteria (NTM) and Mycobacterium tuberculosis, are pathogens of significant worldwide interest owing to their inherent drug resistance to a wide variety of FDA-approved drugs as well as causing a broad range of serious infections. Identifying new antibiotics active against mycobacterial pathogens is an urgent unmet need, especially those antibiotics that can bypass existing resistance mechanisms. In this study, we demonstrate that gepotidacin, a first-in-class triazaacenapthylene topoisomerase inhibitor, demonstrates potent activity against M. tuberculosis and M. fortuitum, as well as against other clinically relevant NTM species, including fluoroquinolone-resistant M. abscessus. Furthermore, gepotidacin exhibits concentration-dependent bactericidal activity against various mycobacterial pathogens, synergizes with several drugs utilized for their treatment, and reduces bacterial load in macrophages in intracellular killing assays comparably to amikacin. Additionally, M. fortuitum ATCC 6841 was unable to generate resistance to gepotidacin in vitro. When tested in a murine neutropenic M. fortuitum infection model, gepotidacin caused a significant reduction in bacterial load in various organs at a 10-fold lower concentration than amikacin. Taken together, these findings show that gepotidacin possesses a potentially new mechanism of action that enables it to escape existing resistance mechanisms. Thus, it can be projected as a potent novel lead for the treatment of mycobacterial infections, particularly for NTM, where present therapeutic interventions are extremely limited.


Assuntos
Infecções por Mycobacterium não Tuberculosas , Mycobacterium tuberculosis , Neutropenia , Animais , Camundongos , Amicacina/farmacologia , Amicacina/uso terapêutico , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Micobactérias não Tuberculosas , Neutropenia/tratamento farmacológico , Testes de Sensibilidade Microbiana
3.
Malar J ; 19(1): 214, 2020 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-32571333

RESUMO

BACKGROUND: Vivax malaria is associated with significant morbidity and economic loss, and constitutes the bulk of malaria cases in large parts of Asia and South America as well as recent case reports in Africa. The widespread prevalence of vivax is a challenge to global malaria elimination programmes. Vivax malaria control is particularly challenged by existence of dormant liver stage forms that are difficult to treat and are responsible for multiple relapses, growing drug resistance to the asexual blood stages and host-genetic factors that preclude use of specific drugs like primaquine capable of targeting Plasmodium vivax liver stages. Despite an obligatory liver-stage in the Plasmodium life cycle, both the difficulty in obtaining P. vivax sporozoites and the limited availability of robust host cell models permissive to P. vivax infection are responsible for the limited knowledge of hypnozoite formation biology and relapse mechanisms, as well as the limited capability to do drug screening. Although India accounts for about half of vivax malaria cases world-wide, very little is known about the vivax liver stage forms in the context of Indian clinical isolates. METHODS: To address this, methods were established to obtain infective P. vivax sporozoites from an endemic region in India and multiple assay platforms set up to detect and characterize vivax liver stage forms. Different hepatoma cell lines, including the widely used HCO4 cells, primary human hepatocytes as well as hepatocytes obtained from iPSC's generated from vivax patients and healthy donors were tested for infectivity with P. vivax sporozoites. RESULTS: Both large and small forms of vivax liver stage are detected in these assays, although the infectivity obtained in these platforms are low. CONCLUSIONS: This study provides a proof of concept for detecting liver stage P. vivax and provide the first characterization of P. vivax liver stage forms from an endemic region in India.


Assuntos
Estágios do Ciclo de Vida , Fígado/parasitologia , Malária Vivax/parasitologia , Plasmodium vivax/crescimento & desenvolvimento , Índia , Plasmodium vivax/isolamento & purificação
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