AbstractTheMycobacterium abscessuscomplex is a group of emerging pathogens that are difficult to treat. There are no effective drugs for successfulM. abscessuspulmonary infection therapy, and existing drug regimens recommended by the British or the American Thoracic Societies are associated with poor clinical outcomes. Therefore, novel antibacterial drugs are urgently needed to contain this global threat. The current anti‐M. abscessussmall‐molecule drug development process can be enhanced by two parallel strategies—discovery of compounds from new chemical classes and commercial drug repurposing. This review focuses on recent advances in the finding of novel small‐molecule agents, and more particularly focuses on the activity, mode of action and structure–activity relationship of promising inhibitors from five different chemical classes—benzimidazoles, indole‐2‐carboxamides, benzothiazoles, 4‐piperidinoles, and oxazolidionones. We further discuss some other interesting small molecules, such as thiacetazone derivatives and benzoboroxoles, that are in the early stages of drug development, and summarize current knowledge about the efficacy of repurposable drugs, such as rifabutin, tedizolid, bedaquiline, and others. We finally review targets of therapeutic interest inM. abscessus that may be worthy of future drug and adjunct therapeutic development.

2021-03-12·ACS Infectious Diseases2区 · 医学

A Coumarin-Based Analogue of Thiacetazone as Dual Covalent Inhibitor and Potential Fluorescent Label of HadA in Mycobacterium tuberculosis

2区 · 医学

Article

作者: Grzegorzewicz, Anna ; Chassaing, Stefan ; Seguin, Cendrine ; Farjallah, Asma ; Záhorszká, Monika ; Abid, Souhir ; Jackson, Mary ; Carayon, Chantal ; Danel, Mathieu ; Peixoto, Antonio ; Goncalves, Fernanda ; Fumagalli, Marco ; Vega, Elodie ; Chiarelli, Laurent R. ; Pasca, Maria Rosalia ; Degiacomi, Giulia ; Forbak, Martin ; Lherbet, Christian ; Korduláková, Jana

A novel coumarin-based molecule, designed as a fluorescent surrogate of a thiacetazone-derived antitubercular agent, was quickly and easily synthesized from readily available starting materials. This small molecule, coined Coum-TAC, exhibited a combination of appropriate physicochemical and biological properties, including resistance toward hydrolysis and excellent antitubercular efficiency similar to that of well-known thiacetazone derivatives, as well as efficient covalent labeling of HadA, a relevant therapeutic target to combat Mycobacterium tuberculosis. More remarkably, Coum-TAC was successfully implemented as an imaging probe that is capable of labeling Mycobacterium tuberculosis in a selective manner, with an enrichment at the level of the poles, thus giving for the first time relevant insights about the polar localization of HadA in the mycobacteria.

2020-01-01·Ceska a Slovenska farmacie : casopis Ceske farmaceuticke spolecnosti a Slovenske farmaceuticke spolecnosti

Focus on perchlozone, an anti-tuberculosis drug from the Russian Federation.

Article

作者: Čižmárik, Jozef ; Pecháčová, Mária ; Malík, Ivan

The prevalence of multidrug-resistant tuberculosis (MDR--TB) and extensively drug-resistant tuberculosis (XDR--TB) has been increasing at an alarming rate worldwide. Todays “Fight against Tuberculosis“ programmes in the Russian Federation are subsidized by state and regional governments as well as health authorities. Each region has its own specific characteristics and needs specific interventions. Although some novel anti-tuberculosis (anti-TB) drugs (bedaquiline, delamanid) were approved by relevant authorities, and some promising compounds, especially those of oxazolidinones, are in various phases of clinical trials worldwide, the finding of effective, safe, pharmacokinetically favo-rable, economically and logistically accessible anti-TB agents still remains a serious challenge for medical and pharmaceutical sciences. Perchlozone, a compound containing a thiosemicarbazone scaffold, was approved in the Russian Federation in 2012 for the treatment (alone or as the active component of complex treatment regimens) of HIV-1 negative as well as HIV-1 positive patients suffering from MDR-TB or XDR-TB. Mechanism of anti-TB action of perchlozone might be similar to that of thiacetazone, which belongs into the same chemical class. Perchlozone has to be probably activated into reactive species by a mycobacterially encoded monoxygenase (EthA). The activated forms might act in multiple ways, including inhibition of mycobacterial cell wall synthesis due to interfence with a dehydration step of the type II fatty acid synthase pathway or sensitization of the Mycobacterium tuberculosis cell to oxidative stress. Favorable toxicological properties of perchlozone and its tolerability by the human organism were confirmed within revevant preclinical and clinical studies. However, recent preliminary investigations in vivo (animal models) could indicate genotoxicity after subacute inhalation of the drug. Regarding this issue, further development of more convenient nano- or microparticle-based formulations of perchlozone potentially improving targeted delivering and efficiency as well as decreasing (eliminating) its eventual toxicity might be taken into strong consideration.

100 项与 KBF-611 相关的药物交易

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