Repurposing of statins for Buruli Ulcer treatment: antimicrobial activity against Mycobacterium ulcerans.

Mycobacterium ulcerans causes Buruli Ulcer, a neglected infectious skin disease that typically progresses from an early non-ulcerative lesion to an ulcer with undermined edges. If not promptly treated, these lesions can lead to severe disfigurement and disability. The standard antibiotic regimen for Buruli Ulcer treatment has been oral rifampicin combined with intramuscular streptomycin administered daily for 8 weeks. However, there has been a recent shift toward replacing streptomycin with oral clarithromycin. Despite the advantages of this antibiotic regimen, it is limited by low compliance, associated side effects, and refractory efficacy for severe ulcerative lesions. Therefore, new drug candidates with a safer pharmacological spectrum and easier mode of administration are needed. Statins are lipid-lowering drugs broadly used for dyslipidemia treatment but have also been reported to have several pleiotropic effects, including antimicrobial activity against fungi, parasites, and bacteria. In the present study, we tested the susceptibility of M. ulcerans to several statins, namely atorvastatin, simvastatin, lovastatin and fluvastatin. Using broth microdilution assays and cultures of M. ulcerans-infected macrophages, we found that atorvastatin, simvastatin and fluvastatin had antimicrobial activity against M. ulcerans. Furthermore, when using the in vitro checkerboard assay, the combinatory additive effect of atorvastatin and fluvastatin with the standard antibiotics used for Buruli Ulcer treatment highlighted the potential of statins as adjuvant drugs. In conclusion, statins hold promise as potential treatment options for Buruli Ulcer. Further studies are necessary to validate their effectiveness and understand the mechanism of action of statins against M. ulcerans.

Development of an antibiotics delivery system for topical treatment of the neglected tropical disease Buruli ulcer.

Skin infection by Mycobacterium ulcerans causes Buruli ulcer (BU) disease, a serious condition that significantly impact patient' health and quality of life and can be very difficult to treat. Treatment of BU is based on daily systemic administration of antibiotics for at least 8 weeks and presents drawbacks associated with the mode and duration of drug administration and potential side effects. Thus, new therapeutic strategies are needed to improve the efficacy and modality of BU therapeutics, resulting in a more convenient and safer antibiotic regimen. Hence, we developed a dual delivery system based on poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) microparticles and a gellan gum (GG) hydrogel for delivery of rifampicin (RIF) and streptomycin (STR), two antibiotics used for BU treatment. RIF was successfully loaded into PHBV microparticles, with an encapsulation efficiency of 43%, that also revealed a mean size of 10 µm, spherical form and rough topography. These microparticles were further embedded in a GG hydrogel containing STR. The resultant hydrogel showed a porous microstructure that conferred a high water retention capability (superior to 2000%) and a controlled release of both antibiotics. Also, biological studies revealed antibacterial activity against M. ulcerans, and a good cytocompatibility in a fibroblast cell line. Thus, the proposed drug delivery system can constitute a potential topical approach for treatment of skin ulcers caused by BU disease.

Evaluation of the clinical significance of homB, a novel candidate marker of Helicobacter pylori strains associated with peptic ulcer disease.

BACKGROUND: homB codes for a putative Helicobacter pylori outer membrane protein and has previously been associated with peptic ulcer disease (PUD) in children. METHODS: A total of 190 H. pylori strains isolated from children and adults were studied to evaluate the clinical importance of the homB gene. In vitro experiments were performed to identify HomB mechanisms of bacterial pathogenicity. RESULTS: Characterization of the isolates demonstrated that homB was significantly associated with PUD in 86 children (odds ratio [OR], 7.64 [95% confidence interval {CI}, 2.65-22.05]) and in 32 adults < or =40 years of age (OR, 11.25 [95% CI, 1.86-68.13]). homB was correlated with the presence of cagA, babA2, vacAs1, hopQI, and oipA "on" genotype (P< .001) The HomB protein was found to be expressed in the H. pylori outer membrane and was noted to be antigenic in humans. H. pylori homB knockout mutant strains presented reduced ability to induce interleukin-8 secretion from human gastric epithelial cells, as well as reduced capacity to bind to these cells. Both of these functions correlated with the number of homB copies present in a strain. CONCLUSION: homB can be considered a comarker of H. pylori strains associated with PUD. Moreover, results strongly suggest that HomB is involved in the inflammatory response and in H. pylori adherence, constituting a novel putative virulence factor.