rifampin and Hypoxia

The stalling development of antibiotics, especially against intrinsically resistant Gram-negative pathogens associated with outer membranes, leads to an emerging antibiotic crisis across the globe. To breathe life into existing drugs, we herein report a hypoxia-responsive nanoparticle (NP) that encapsulates a hydrophobic antibiotic, rifampicin, and a cationic potentiator, polysulfonium. The simultaneous release of antibiotics and potentiators can be promoted and inhibited in response to the severity of bacterial-induced hypoxia, leading to antimicrobial dosing in a precision manner. Under the synergism of polysulfoniums with membrane-disruption capability, the NPs can intensively decrease the antibiotic dose by up to 66-95% in eliminating planktonic Gram-negative

Topics: Anti-Bacterial Agents; Drug Resistance, Microbial; Gram-Negative Bacteria; Humans; Hypoxia; Nanoparticles; Rifampin

The activities of rifampin, nitazoxanide, PA-824, and sutezolid were tested against dormant

Topics: Antitubercular Agents; Drug Combinations; Drug Therapy, Combination; Ethambutol; Humans; Hydrogen-Ion Concentration; Hypoxia; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nitroimidazoles; Oxazolidinones; Pyrazinamide; Rifampin; Tuberculosis

During active TB in humans a spectrum of pulmonary granulomas with central necrosis and hypoxia exists. BALB/c mice, predominantly used in TB drug development, do not reproduce this complex pathology thereby inaccurately predicting clinical outcome. We found that Nos2

Topics: Animals; Antitubercular Agents; Disease Models, Animal; Fibrosis; Foam Cells; Humans; Hypoxia; Isoniazid; Mice; Mice, Knockout; Necrosis; Nitric Oxide Synthase Type II; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

Chronic intermittent hypoxia is the most important pathophysiologic feature of sleep apnea syndrome. The present study aimed to determine whether chronic intermittent hypoxia, which is associated with sleep apnea syndrome, can cause or increase damage to liver cell ultrastructure induced by isoniazid and rifampicin in mice.. Based on a 2 × 2 full factorial design consisting of two factors of chronic intermittent hypoxia and isoniazid plus rifampicin, 32 male C57B6J mice were randomized into the control group, the chronic intermittent hypoxia group, the isoniazid plus rifampicin group, and the chronic intermittent hypoxia + isoniazid plus rifampicin group. Twelve weeks after treatment, we examined the ultrastructure of liver cells and quantitatively analyzed mitochondrial morphology in C57B6J mice.. Chronic intermittent hypoxia did not significantly affect the ultrastructure of liver cells. The main effect of chronic intermittent hypoxia did not lead to an increase of mean profile area or mean perimeter of mitochondria, and a decrease of numerical density on area of mitochondria (all P > 0.05). Isoniazid plus rifampicin significantly affected liver cell ultrastructure. The main effect of isoniazid plus rifampicin resulted in an increase of mean profile area and mean perimeter of mitochondria, and a decrease of numerical density on area of mitochondria (all P < 0.05). Moreover, there was a positive interaction among the chronic intermittent hypoxia and the isoniazid plus rifampicin groups for mean profile area, mean perimeter, and numerical density on area of mitochondria (all P < 0.05).. Chronic intermittent hypoxia and isoniazid plus rifampicin treatment lead to synergistic liver cell ultrastructural injury.

Topics: Animals; Hypoxia; Isoniazid; Liver; Male; Mice; Mice, Inbred C57BL; Microscopy, Electron, Transmission; Rifampin; Sleep Apnea Syndromes

The lengthy chemotherapy of tuberculosis reflects the ability of a small subpopulation of Mycobacterium tuberculosis bacteria to persist in infected individuals. To date, the exact location of these persisting bacteria is not known. Lung lesions in guinea pigs infected with M. tuberculosis have striking similarities, such as necrosis, mineralization, and hypoxia, to natural infections in humans. Guinea pigs develop necrotic primary lesions after aerosol infection that differ in their morphology compared to secondary lesions resulting from hematogenous dissemination. In infected guinea pigs conventional therapy for tuberculosis during 6 weeks reduced the bacterial load by 1.7 logs in the lungs and, although this completely reversed lung inflammation associated with secondary lesions, the primary granulomas remained largely unaffected. Treatment of animals with the experimental drug R207910 (TMC207) for 6 weeks was highly effective with almost complete eradication of the bacteria throughout both the primary and the secondary lesions. Most importantly, the few remnants of acid-fast bacilli remaining after R207910 treatment were to be found extracellular, in a microenvironment of residual primary lesion necrosis with incomplete dystrophic calcification. This zone of the primary granuloma is hypoxic and is morphologically similar to what has been described for human lung lesions. These results show that this acellular rim may, therefore, be a primary location of persisting bacilli withstanding drug treatment.

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Colony Count, Microbial; Diarylquinolines; Female; Granuloma; Guinea Pigs; Hypoxia; Isoniazid; Lung; Mycobacterium tuberculosis; Nitroimidazoles; Pyrazinamide; Quinolines; Radiation-Sensitizing Agents; Rifampin; Spleen; Tuberculosis