Abstract
Microbial biofilms have been recognized for a vital role in antibiotic resistance and chronic microbial infections for 2-3 decades; still, there are no 'anti-biofilm drugs' available for human applications. There is an urgent need to develop novel 'anti-biofilms' therapeutics to manage biofilm-associated infectious diseases. Several reports have suggested that targeting molecules involved in quorum sensing or biofilm-specific transcription may inhibit biofilm formation. However, the possibility of targeting other vital components of microbial biofilms, especially the extracellular matrix (ECM) components, has remained largely unexplored. Here we report targeting TasA(28-261), the major proteinaceous component of Bacillus subtilis ECM with two small molecule inhibitors (lovastatin and simvastatin) identified through virtual screening and drug repurposing, resulted in complete inhibition of biofilm. In molecular docking and dynamics simulation studies, lovastatin was observed to make stable interactions with TasA(28-261), whereas the simvastatin – TasA(28-261) interactions were relatively less stable. However, in subsequent in vitro studies, both lovastatin and simvastatin successfully inhibited B. subtilis biofilm formation at MIC values of < 10 µg/ml. Besides, these potential inhibitors also caused the disintegration of pre-formed biofilms. Results presented here provide ‘proof of concept’ for the hypothesis that targeting the extracellular matrix's vital component(s) could be one of the most efficient approaches for inhibiting microbial biofilms and disintegrating the pre-formed biofilms. We propose that a similar approach targeting ECM-associated proteins with FDA-approved drugs could be implemented to develop novel anti-biofilm therapeutic strategies against biofilm-forming chronic microbial pathogens.
Communicated by Ramaswamy H. Sarma
Disclosure statement
No potential conflict of interest was reported by the authors.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Availability of data and material
All relevant data are within the paper. The same is available for any future academic/research activity.
Code availability
The softwares used during the present study either commercially available or freely available resources. We are happy to share codes/resource information for freely available resource.
Authors' contribution
JP conceieved the scientific idea of the study and arranged for necessary reagents, equipments etc for execution of the study. NV carried out experiments, collected raw data and processed it. SS and RM carried out the MD simulation studies at extended time durations. RM, PG and JP analysed the experimental data (raw data and processed data). NV and JP wrote the manuscript. All the authors assessed and approved the manuscript for submission.