Jigneshkumar Dahyabhai Prajapati

• The outer membrane of the Gram-negative microbes imposes a permeability barrier for solutes located in the external environment. Integral membrane channels positioned along the outer membrane fulfill the task of nutrient translocation to the periplasm. Additionally, these channels are also known to be involved in the antibiotics uptake. However, the permeation routes taken by most classes of antibiotics remain unknown since their discovery. The studies reported in this thesis have been carried out to elaborate the molecular level understanding of the translocation of large solutes, i.e., substrates and antibiotics, through specific and non-specific channels using "state of the art" methods in all-atom molecular dynamics (MD) simulations. The first part of the thesis includes an investigation on the translocation of the fluoroquinolone class of antibiotics, especially of ciprofloxacin and enrofloxacin molecules, through the porin OmpC of Escherichia coli. In the second part, the permeation of bulky cylcodextrin molecules through the specific channel CymA from Klebsiella oxytoca is investigated. Moreover, we have estimated the EOF using various salts and illustrated its influence on the α-CD interaction with the ∆CymA channel at an atomistic scale. In the final study, we have investigated the transport properties of the putative dicarboxylate specific channel DcaP from the pathogen Acinetobacter baumannii. Overall, the findings presented in this thesis improve the atomistic understanding of the permeation of substrates and antibiotics through outer membrane channels of Gram-negative bacteria. Moreover, building such structure-function relationship of various outer membrane channels will help to develop future antimicrobials with enhanced permeability.