Part of the book: Medicinal Chemistry and Drug Design
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is a leading cause of death in humans worldwide. The emergence of antibiotic-resistant strains of Mtb is a threat to tuberculosis control. A general belief is that drug resistance is acquired by Mtb during antibiotic treatment by accumulation of spontaneous mutations. Also, it is known that the drug resistance mutations (DRM) have an associated fitness cost, reducing the transmissibility and virulence of resistant strains. In this work we show that many canonical DRM are clade specific; i.e. they occur only in specific genetic lineages of Mtb and depend on a specific genetic context necessary for the reduction of the fitness cost and sustainability of the drug resistance phenotype. Dependence of the drug resistance on occurrence of genetic variants of multiple genes and specific activities of the encoded proteins allows combating the drug resistance by impairing the global genetic context. A new drug, FS-1, reverses antibiotic resistance by compromising this genetic context and aggravating the fitness cost of DRM.
Part of the book: Basic Biology and Applications of Actinobacteria
The new iodine complex (FS-1), including molecular iodine, which is coordinated by lithium, magnesium halides, and bioorganic ligands, possesses high bactericidal activity against various microorganisms, including Mycobacterium sp., Staphylococcus aureus MRSA and MSSA, Escherichia coli, Pseudomonas aeruginosa, etc. FS-1 has synergistic properties with a broad class of antibiotics. The experimental model of tuberculosis in guinea pigs caused by clinical multidrug-resistant strains of Mycobacterium tuberculosis shows antituberculosis, immunomodulatory, and anti-inflammatory activity. FS-1 is characterized by low acute toxicity and lack of genotoxicity and mutagenicity. FS-1 is well distributed to organs and tissues; its pharmacokinetics is linear. The maximum nontoxic dose is 100 mg/kg for rats after 28-day oral administration and 30 mg/kg for rabbits after 180-day oral administration.
Part of the book: Medicinal Chemistry