Cu-promoted synthesis of triclosan-Mannich and Glaser adducts: anti-mycobacterial evaluation with validations.

 The WHO, Global tuberculosis report 2022 estimated number of tuberculosis (TB) cases reached 10.6 million in 2021, reflecting a 4.5% increase compared with the 10.

Evaluation and activity of new porphyrin-peptide cage-type conjugates for the photoinactivation of .

is increasingly recognized as an emerging opportunistic pathogen causing severe lung diseases and cutaneous infections. However, treatment of infections remains particularly challenging, largely due to intrinsic resistance to a wide panel of antimicrobial agents. New therapeutic alternatives are urgently needed.

High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against nontuberculous mycobacteria in vitro and in vivo.

The FF-ATP synthase engine is essential for viability and growth of nontuberculous mycobacteria (NTM) by providing the biological energy ATP and keeping ATP homeostasis under hypoxic stress conditions. Here, we report the discovery of the diarylquinoline TBAJ-5307 as a broad spectrum anti-NTM inhibitor, targeting the F domain of the engine and preventing rotation and proton translocation. TBAJ-5307 is active at low nanomolar concentrations against fast- and slow-growing NTM as well as clinical isolates by depleting intrabacterial ATP.

Tailoring selective triclosan azo-adducts: Design, synthesis, and anti-mycobacterial evaluation.

A series of triclosan azo-adducts were synthesized to investigate their structure-activity relationship against and non-tuberculous mycobacteria. The series' most potent compound was four and sixteen times more active than triclosan and rifabutin against drug-resistant , respectively, while being less cytotoxic to human macrophages than triclosan on day one. Additionally, one of the azo-adducts was twice as efficient against as triclosan and twice as effective against as isoniazid.

Silencing essential gene expression in during infection.

represents the most common rapidly growing mycobacterial pathogen in cystic fibrosis and is extremely difficult to eradicate. Essential genes are required for growth, often participate in pathogenesis, and encode valid drug targets for further chemotherapeutic developments. However, assessing the function of essential genes in remains challenging due to the limited spectrum of efficient genetic tools.

New therapeutic strategies for pulmonary diseases - untapping the mycolic acid pathway.

Introduction: Treatment options against infections are very limited. New compounds are needed to cure pulmonary diseases. While the mycolic acid biosynthetic pathway has been largely exploited for the treatment of tuberculosis, this metabolic process has been overlooked in , although it offers many potential drug targets for the treatment of this opportunistic pathogen.

and Efficacy of NITD-916 against Mycobacterium fortuitum.

Mycobacterium fortuitum represents one of the most clinically relevant rapid-growing mycobacterial species. Treatments are complex due to antibiotic resistance and to severe side effects of effective drugs, prolonged time of treatment, and co-infection with other pathogens. Herein, we explored the activity of NITD-916, a direct inhibitor of the enoyl-ACP reductase InhA of the type II fatty acid synthase in Mycobacterium tuberculosis.

Synthesis and Testing of Analogs of the Tuberculosis Drug Candidate SQ109 against Bacteria and Protozoa: Identification of Lead Compounds against and Malaria Parasites.

SQ109 is a tuberculosis drug candidate that has high potency against and is thought to function at least in part by blocking cell wall biosynthesis by inhibiting the MmpL3 transporter. It also has activity against bacteria and protozoan parasites that lack MmpL3, where it can act as an uncoupler, targeting lipid membranes and Ca homeostasis. Here, we synthesized 18 analogs of SQ109 and tested them against , , , , and , as well as against the protozoan parasites , , , , and .

Efficacy and Mode of Action of a Direct Inhibitor of InhA.

There is an unmet medical need for effective treatments against pulmonary infections, to which cystic fibrosis (CF) patients are particularly vulnerable. Recent studies showed that the antitubercular drug isoniazid is inactive against due to the incapacity of the catalase-peroxidase to convert the pro-drug into a reactive metabolite that inhibits the enoyl-ACP reductase InhA. To validate InhA as a druggable target in , we assayed the activity of NITD-916, a 4-hydroxy-2-pyridone lead candidate initially described as a direct inhibitor of InhA that bypasses KatG bioactivation in .

Designing quinoline-isoniazid hybrids as potent anti-tubercular agents inhibiting mycolic acid biosynthesis.

Isoniazid is a cornerstone of modern tuberculosis (TB) therapy and targets the enoyl ACP reductase InhA, a key enzyme in mycolic acid biosynthesis. InhA is still a promising target for the development of new anti-TB drugs. Herein, we report the design, synthesis, and anti-tubercular activity of new isoniazid hybrids.

[Mycobacterium abscessus, a model of resistance to multiple antibiotic classes].

Mycobacterium abscessus is an environmental fast-growing, non-tuberculous mycobacterium responsible for severe lung infections, especially in patients with underlying lung disorders such as cystic fibrosis. The standard chemotherapy combines a b-lactam (imipenem or cefoxitin), an aminoglycoside (amikacin) and a macrolide (clarithromycin or azithromycin). However, resistance of this bacterium to most antibiotic classes, including nearly all anti-tubercular drugs, leads frequently to treatment failure and considerably reduces the therapeutic arsenal available to the clinician.

Mycobacteriophage-antibiotic therapy promotes enhanced clearance of drug-resistant Mycobacterium abscessus.

Infection by multidrug-resistant Mycobacterium abscessus is increasingly prevalent in cystic fibrosis (CF) patients, leaving clinicians with few therapeutic options. A compassionate study showed the clinical improvement of a CF patient with a disseminated M. abscessus (GD01) infection, following injection of a phage cocktail, including phage Muddy.

Rifabutin Is Bactericidal against Intracellular and Extracellular Forms of Mycobacterium abscessus.

is increasingly recognized as an emerging opportunistic pathogen causing severe lung diseases. As it is intrinsically resistant to most conventional antibiotics, there is an unmet medical need for effective treatments. Repurposing of clinically validated pharmaceuticals represents an attractive option for the development of chemotherapeutic alternatives against infections.