BITS Faculty Publications

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    Characterization of ciprofloxacin permeation pathways across the Porin OmpC using metadynamics and a string method
    (ACS, 2017-08) Prajapati, Jigneshkumar Dahyabhai
    The rapid spreading of antimicrobial resistance in Gram-negative bacteria has become a major threat for humans as well as animals. As one of the main factors involved, the permeability of the outer membrane has attracted a great deal of attention recently. However, the knowledge regarding the translocation mechanisms for most available antibiotics is so far rather limited. Here, a theoretical study concerning the diffusion route of ciprofloxacin across the outer membrane porin OmpC from E. coli is presented. To this end, we establish a protocol to characterize meaningful permeation pathways by combining metadynamics with the zero-temperature string method. It was found that the lowest-energy pathway requires a reorientation of ciprofloxacin in the extracellular side of the porin before reaching the constriction region with its carboxyl group ahead. Several affinity sites have been identified, and their metastability has been evaluated using unbiased simulations. Such a detailed understanding is potentially very helpful in guiding the development of next generation antibiotics.
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    Atomistic simulation of molecules interacting with biological nanopores: from current understanding to future directions
    (ACS, 2022-05) Prajapati, Jigneshkumar Dahyabhai
    Biological nanopores have been at the focus of numerous studies due to their role in many biological processes as well as their (prospective) technological applications. Among many other topics, recent studies on nanopores have addressed two key areas: antibiotic permeation through bacterial channels and sensing of analytes. Although the two areas are quite far apart in terms of their objectives, in both cases atomistic simulations attempt to understand the solute dynamics and the solute–protein interactions within the channel lumen. While decades of studies on various channels have culminated in an improved understanding of the key molecular factors and led to practical applications in some cases, successful utilization is limited. In this Perspective we summarize recent progress in understanding key issues in molecular simulations of antibiotic translocation and in the development of nanopore sensors. Moreover, we comment on possible advancements in computational algorithms that can potentially resolve some of the issues.
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    Conformational dynamics of loop L3 in OMPF: implications toward antibiotic translocation and voltage gating
    (ACS, 2022-12) Prajapati, Jigneshkumar Dahyabhai
    In the present work, we delineate the molecular mechanism of a bulky antibiotic permeating through a bacterial channel and uncover the role of conformational dynamics of the constriction loop in this process. Using the temperature accelerated sliced sampling approach, we shed light onto the dynamics of the L3 loop, in particular the F118 to S125 segment, at the constriction regions of the OmpF porin. We complement the findings with single channel electrophysiology experiments and applied-field simulations, and we demonstrate the role of hydrogen-bond stabilization in the conformational dynamics of the L3 loop. A molecular mechanism of permeation is put forward wherein charged antibiotics perturb the network of stabilizing hydrogen-bond interactions and induce conformational changes in the L3 segment, thereby aiding the accommodation and permeation of bulky antibiotic molecules across the constriction region. We complement the findings with single channel electrophysiology experiments and demonstrate the importance of the hydrogen-bond stabilization in the conformational dynamics of the L3 loop. The generality of the present observations and experimental results regarding the L3 dynamics enables us to identify this L3 segment as the source of gating. We propose a mechanism of OmpF gating that is in agreement with previous experimental data that showed the noninfluence of cysteine double mutants that tethered the L3 tip to the barrel wall on the OmpF gating behavior. The presence of similar loop stabilization networks in porins of other clinically relevant pathogens suggests that the conformational dynamics of the constriction loop is possibly of general importance in the context of antibiotic permeation through porins.
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    Antibacterial and antiviral materials based on biodegradable polymers
    (ACS, 2023-12) Jain, Ankit
    Antibacterial and antiviral materials based on biodegradable polymers have become a key area of research in recent years due to the increasing concern over bacterial and viral infections. Biodegradable polymers are attractive for medical applications due to their biocompatibility, biodegradability, and low toxicity. They can be used to produce various antibacterial and antiviral materials such as films, coatings, and nanoparticles. These materials can be used for medical implants, wound dressings, drug delivery systems, and personal protective equipment. Several strategies have been employed to develop antibacterial and antiviral materials based on biodegradable polymers. One approach is to incorporate antimicrobial agents into the polymer matrix, such as nanoparticles, and antibiotics. This chapter focuses on the different antibacterial and antiviral materials based on biodegradable polymers and the application of NPs developed from such materials. The mechanisms of action and performance of these materials against bacteria and viruses are discussed. The challenges and prospects of using these materials are also discussed. The potential of these materials to provide effective and sustainable solutions to combat bacterial and viral infections makes them a promising area of research for the development of new antimicrobial materials.
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    Basic Nitrogen (BaN) Is a Key Property of Antimalarial Chemical Space
    (ACS, 2023-06) Sundriyal, Sandeep
    Most antimalarials are based on basic N-heterocycles and possess amine functionalities. Despite this, the role of basic nitrogen (BaN) in antimalarial drug design has not been studied systematically. Our cheminformatics analysis indicates that BaN is an important feature of antimalarial space. We show that potent research antiplasmodials (RAP) and advanced-stage antimalarials (ASAMs) consistently show a higher BaN count (#BaN) compared to oral drugs. Similarly, BaN is often a vital feature of the hits obtained from phenotypic screenings despite the use of varied assay conditions. The literature review demonstrates that in several unrelated scaffolds, the addition of BaN results in enhanced antiplasmodial activity. In addition, potent antiplasmodials and HTS hits are bulky, lipophilic, and less polar and have a high aromatic ring count (#AR). This characterization of antimalarial space may be used to collate a focused compound collection to achieve higher hit rates in HTS, as shown retrospectively in this perspective.
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    Physicochemical Profiling and Comparison of Research Antiplasmodials and Advanced Stage Antimalarials with Oral Drugs
    (ACS, 2021-02) Sundriyal, Sandeep
    To understand the property space of antimalarials, we collated a large dataset of research antiplasmodial (RAP) molecules with known in vitro potencies and advanced stage antimalarials (ASAMs) with established oral bioavailability. While RAP molecules are “non-druglike”, ASAM molecules display properties closer to Lipinski’s and Veber’s thresholds. Comparison within the different potency groups of RAP molecules indicates that the in vitro potency is positively correlated to the molecular weight, the calculated octanol–water partition coefficient (clog P), aromatic ring counts (#Ar), and hydrogen bond acceptors. Despite both categories being bioavailable, the ASAM molecules are relatively larger and more lipophilic, have a lower polar surface area, and possess a higher count of heteroaromatic rings than oral drugs. Also, antimalarials are found to have a higher proportion of aromatic (#ArN) and basic nitrogen (#BaN) counts, features implicitly used in the design of antimalarial molecules but not well studied hitherto. We also propose using descriptors scaled by the sum of #ArN and #BaN (SBAN) to define an antimalarial property space. Together, these results may have important applications in the identification and optimization of future antimalarials.
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    Design and Synthesis of Imidazo/Benzimidazo[1,2-c]quinazoline Derivatives and Evaluation of Their Antimicrobial Activity
    (ACS, 2018) Jha, Prabhat N.; Kumar, Anil
    A new class of fused quinazolines has been designed and synthesized via copper-catalyzed Ullmann type C–N coupling followed by intramolecular cross-dehydrogenative coupling reaction in moderate to good yields. The synthesized compounds were tested for in vitro antibacterial activity against three Gram negative (Escherichia coli, Pseudomonas putida, and Salmonella typhi) and two Gram positive (Bacillus subtilis, and Staphylococcus aureus) bacteria. Among all tested compounds, 8ga, 8gc, and 8gd exhibited promising minimum inhibitory concentration (MIC) values (4–8 μg/mL) for all bacterial strains tested as compared to the positive control ciprofloxacin. The synthesized compounds were also evaluated for their in vitro antifungal activity against Aspergillus niger and Candida albicans and compounds 8ga, 8gc, and 8gd having potential antibacterial activity also showed pronounced antifungal activity (MIC values 8–16 μg/mL) against both strains. The bactericidal assay by propidium iodide and live–dead bacterial cell screening using a mixture of acridine orange/ethidium bromide (AO/Et·Br) showed considerable changes in the bacterial cell membrane, which might be the cause or consequence of cell death. Moreover, the hemolytic activity for most potent compounds (8ga, 8gc, and 8gd) showed their safety profile toward human blood cells.