Shamik Ghosh

New antibiotics should ideally exhibit activity against drug-resistant bacteria, delay the development of bacterial resistance to them and be suitable for local delivery at desired sites of infection. Here, we report the rational design, via molecular-docking simulations, of a library of 17 candidate antibiotics against bone infection by wild-type and mutated bacterial targets. We screened this library for activity against multidrug-resistant clinical isolates and identified an antibiotic that exhibits potent activity against resistant strains and the formation of biofilms, decreases the chances of bacterial resistance and is compatible with local delivery via a bone-cement matrix. The antibiotic-loaded bone cement exhibited greater efficacy than currently used antibiotic-loaded bone cements against staphylococcal bone infections in rats. Potent and locally delivered antibiotic-eluting polymers may help address antimicrobial resistance.

Recalcitrant dermatophytic infections of the glabrous skin (tinea corporis/cruris/faciei) pose a huge challenge to health care systems. Combinations of oral and topical drugs may potentially improve cure rates, but the same has never been objectively assessed for this condition in laboratory or clinical studies.

The prevalence of drug-resistant pathogenic fungi is a major global health challenge. There is an urgent need for novel drugs that can exert a potent antifungal activity and overcome resistance. Newly discovered anti-fungal properties of existing compounds can potentially offer a rapid solution to address this persistent threat. We rationalized that structures which disrupt the fungal cell membrane could address the above unmet need. As fatty acids underpin the formation and stability of cell membranes, we used computational simulations to evaluate the interactions between selected short chain fatty acids and a model cell membrane. Here, we report that caprylic acid could penetrate and perturb the membrane in silico. Based on the in silico findings, we identified a derivative of this fatty acid that disrupts fungal membranes as detected using steady-state fluorescence anisotropy. We show that this fatty acid derivative is potent against a variety of fungal pathogens like Candida and Trichophyton. We further demonstrated the ability of this fatty acid derivative to potentiate some azoles in vitro and enhance the efficacy of antifungal formulations in vivo. Our data suggests the emergence of a novel therapy for effective disease management and overcoming anti-fungal drug resistance.

Background: Uninhibited proliferation of Malassezia spp., enhanced sebaceous gland activity and individual sensitivity are three prime etiological factors behind dandruff. For many dandruff sufferers, existing anti-dandruff products start yielding unsatisfactory results after a few cycles of use. This observation made us explore the physical and biological environment of the host and exploit the specific type of lipid dependence of Malassezia spp. for their survival. A shampoo formulation (product code VB-3222) was developed to address the shortcomings of existing therapy. Purpose: Evaluating efficacy of VB-3222 in comparison to marketed products through in vitro assays and subsequently demonstrating its advantages in a clinical study. Methods: VB-3222 was developed with a derivative of medium chain fatty acid (MCFA) and zinc pyrithione and compared against marketed comparators by in vitro time kill assay. Subsequently, VB-3222 shampoo was tested in a 21-day clinical trial on 25 moderate dandruff subjects to evaluate local safety and efficacy. Results: VB-3222 in all in vitro cases demonstrated significantly better fungicidal activity than its marketed comparators. In the clinical trial, VB-3222 was well tolerated in all subjects and imparted consistent reduction of the ASFS (adherent scalp flaking score) and the pruritus score. At days 7 and 21, 55% and 90% reduction in the ASFS in comparison to treatment initiation and 50% and 95.5% reduction in the pruritus score were observed. Conclusion: The increased efficacy of VB-3222 over comparator products in vitro, and the dramatic reduction (> 90%) in ASFS and pruritis in subjects within 21 days of use with excellent tolerability and sensorial profile, positions VB-3222 as the new generation treatment for adherent dandruff. Clinical Trial Registration No: CTRI/2018/05/013567.