Novel FtsZ inhibitor with potent activity against Staphylococcus aureus.

OBJECTIVES: FtsZ is an essential bacterial protein and an unexplored target for the development of antibacterial drugs. The development of a novel inhibitor targeting FtsZ offers a potential opportunity to combat drug resistance. DS01750413, a new derivative of PC190723, is a novel FtsZ inhibitor with improved in vitro and in vivo activity. The objective of this study was to investigate the efficacy of DS01750413 against Staphylococcus spp., including MRSA, in in vitro and in vivo models. METHODS: In vitro activities of DS01750413 and standard-of-care antibiotics were evaluated against clinical isolates of Gram-positive pathogens. The in vivo efficacy was evaluated in a murine systemic infection model caused by MRSA. RESULTS: DS01750413 showed potent in vitro activity against MRSA clinical isolates with MIC ranges of 0.5-1 mg/L and also demonstrated concentration-dependent bactericidal killing. In the murine bacteraemia infection model of MRSA, treatment with DS01750413 resulted in prolonged survival of animals compared with placebo-treated animals and exhibited a significant reduction in the bacterial load in liver, spleen, lungs and kidneys. CONCLUSIONS: DS01750413 showed encouraging in vitro and in vivo activity against MRSA. As a novel chemical class, DS01750413 has the potential to become clinically viable antibiotics to address the drug resistance problem by its unique novel targeting mechanism of action.

Azithromycin Exhibits Activity Against Pseudomonas aeruginosa in Chronic Rat Lung Infection Model.

Pseudomonas aeruginosa forms biofilms in the lungs of chronically infected cystic fibrosis patients, which are tolerant to both the treatment of antibiotics and the host immune system. Normally, antibiotics are less effective against bacteria growing in biofilms; azithromycin has shown a potent efficacy in cystic fibrosis patients chronically infected with P. aeruginosa and improved their lung function. The present study was conducted to evaluate the effect of azithromycin on P. aeruginosa biofilm. We show that azithromycin exhibited a potent activity against P. aeruginosa biofilm, and microscopic observation revealed that azithromycin substantially inhibited the formation of solid surface biofilms. Interestingly, we observed that azithromycin restricted P. aeruginosa biofilm formation by inhibiting the expression of pel genes, which has been previously shown to play an essential role in bacterial attachment to solid-surface biofilm. In a rat model of chronic P. aeruginosa lung infection, we show that azithromycin treatment resulted in the suppression of quorum sensing-regulated virulence factors, significantly improving the clearance of P. aeruginosa biofilms compared to that in the placebo control. We conclude that azithromycin attenuates P. aeruginosa biofilm formation, impairs its ability to produce extracellular biofilm matrix, and increases its sensitivity to the immune system, which may explain the clinical efficacy of azithromycin in cystic fibrosis patients.

Author Correction: Prophylactic potential of cytolethal distending toxin B (CdtB) subunit of typhoid toxin against Typhoid fever.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Prophylactic potential of cytolethal distending toxin B (CdtB) subunit of typhoid toxin against Typhoid fever.

Typhoid fever caused by Salmonella enterica serovar Typhi (S.Typhi) continues to be a major problem, especially in developing countries. Due to the rapid emergence of multi-drug-resistant (MDR) strains, which limits the efficacy of conventional antibiotics as well as problems associated with the existing vaccines, efforts are being made to develop effective prophylactic agents. CdtB subunit of typhoid toxin was selected for assessing its vaccine potential due to its high conservation throughout the Typhi strains. In-vitro assessment of DNase activity of cloned and purified CdtB protein showed a significant decrease in the band intensity of DNA. The measure of metabolic activity and morphological alterations assessed using different cell lines in the presence of CdtB protein showed no significant signs of toxicity. These observations were further strengthened by cell cycle analysis, assessed by flow cytometry. Keeping these observations in mind, the immunoprotective potential of CdtB was assessed using S.Typhi induced mouse peritonitis model. A significant titer of IgG antibodies (>128000) against CdtB protein was recorded in the immunized mice by enzyme-linked immunosorbent assay (ELISA), which was also validated by immunoblotting. Active immunization with the protein protected 75% mice against a lethal dose of S.Typhi Ty2. The data indicated a significant (up to 5 log) reduction in the bacterial load in the spleen and liver of immunized-infected mice compared to control (unimmunized-infected) mice which might have resulted in the modulation of histoarchitecture of spleen and liver and the levels of cytokines (IL-6, TNF-α and IL-10) production; thereby indicating the effectiveness of the subunit. The observations deduced from the study give the proof of concept of immunogenic potential of protein. However, further studies involving the immunoreactivity of CdtB with the statistically significant number of sera samples obtained from the human patients would be helpful in establishing the relevance of CdtB protein in humans and for making the strategies to develop it as an effective vaccine candidate.

DS86760016, a Leucyl-tRNA Synthetase Inhibitor with Activity against Pseudomonas aeruginosa.

DS86760016 is a new leucyl-tRNA-synthetase inhibitor at the preclinical development stage. DS86760016 showed potent activity against extended-spectrum multidrug-resistant Pseudomonas aeruginosa isolated from clinical samples and in vitro biofilms. In a murine catheter-associated urinary tract infection model, DS86760016 treatment resulted in significant eradication of P. aeruginosa from the kidney, bladder, and catheter without developing drug resistance. Our data suggest that DS86760016 has the potential to act as a new drug for the treatment of Pseudomonas infections.

Effect of DS-2969b, a novel GyrB inhibitor, on rat and monkey intestinal microbiota.

DS-2969b, a novel GyrB inhibitor, transiently and reversibly altered the counts of limited intestinal microbiota at around 10 µg/g of faecal levels in rats and monkeys. Considering the high activity of DS-2969b against Clostridium difficile, 10 µg/g of faecal levels would be sufficient for clearing C. difficile from the intestine.