Rationalizing the generation of broad spectrum antibiotics with the addition of a positive charge

Haloi, Nandan; Vasan, Archit Kumar; Geddes, Emily J.; Prasanna, Arjun; Wen, Po‐Chao; Metcalf, William W.; Hergenrother, Paul J.; Tajkhorshid, Emad

doi:10.1039/d1sc04445a

Cited by 20 publications

(24 citation statements)

References 95 publications

(190 reference statements)

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“…More recently, a Monte Carlo pathway search (MCPS) method was described that used a combination of Dijkstra's algorithm and Monte Carlo sampling to obtain an initial path that was used for bias-exchange US simulations. 14 The elevated temperature for the orthogonal degrees of freedom in the TASS formalism enables one to recover the accurate free energy at the system temperature along the CV(s) of interest with improved convergence. 16 For the present system, the center of mass distance between CIP and OmpF projected along the z-axis was selected as the principal CV.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

“…As in case of US, the initial configurations for the TASS simulations can be obtained from a previous steered MD simulation. More recently, a Monte Carlo pathway search (MCPS) method was described that used a combination of Dijkstra’s algorithm and Monte Carlo sampling to obtain an initial path that was used for bias-exchange US simulations . The elevated temperature for the orthogonal degrees of freedom in the TASS formalism enables one to recover the accurate free energy at the system temperature along the CV(s) of interest with improved convergence .…”

Section: Methodsmentioning

confidence: 99%

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Conformational Dynamics of Loop L3 in OmpF: Implications toward Antibiotic Translocation and Voltage Gating

Acharya

Ghai

Piselli

et al. 2022

J. Chem. Inf. Model.

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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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Section: ■ Materials and Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Conformational Dynamics of Loop L3 in OmpF: Implications toward Antibiotic Translocation and Voltage Gating

Acharya

Ghai

Piselli

et al. 2022

J. Chem. Inf. Model.

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“…More recently, Richter et al . 21 identified the presence of a primary amine, flexible bond number (5 or less) and globularity (describing molecular shape), as key features to predict the accumulation of antibiotics in Gram-negative bacteria 22 . Predictive rules of efflux inhibition and avoidance were also identified 23 .…”

Section: Background and Summarymentioning

confidence: 99%

AB-DB: Force-Field parameters, MD trajectories, QM-based data, and Descriptors of Antimicrobials

et al. 2022

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Antibiotic resistance is a major threat to public health. The development of chemo-informatic tools to guide medicinal chemistry campaigns in the efficint design of antibacterial libraries is urgently needed. We present AB-DB, an open database of all-atom force-field parameters, molecular dynamics trajectories, quantum-mechanical properties, and curated physico-chemical descriptors of antimicrobial compounds. We considered more than 300 molecules belonging to 25 families that include the most relevant antibiotic classes in clinical use, such as β-lactams and (fluoro)quinolones, as well as inhibitors of key bacterial proteins. We provide traditional descriptors together with properties obtained with Density Functional Theory calculations. Noteworthy, AB-DB contains less conventional descriptors extracted from μs-long molecular dynamics simulations in explicit solvent. In addition, for each compound we make available force-field parameters for the major micro-species at physiological pH. With the rise of multi-drug-resistant pathogens and the consequent need for novel antibiotics, inhibitors, and drug re-purposing strategies, curated databases containing reliable and not straightforward properties facilitate the integration of data mining and statistics into the discovery of new antimicrobials.

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“…Incorporating the aforementioned insights into structure/ligand-based drug discovery approaches to improve existing antibiotics is a possible way forward. In fact, it was recently demonstrated that introducing an amine moiety into antibacterials such as 6DNM, Ribocil-C, and Debio-1452 results in an extended activity spectrum of these antibiotics from Gram-positive to Gram-negative bacteria. − The same was studied in computational investigations that indicated the role of the interactions of the amine group with the negatively charged residues of the constriction loop . Certainly, molecules that have been screened as potent inhibitors in in vitro binding assays but have failed in antimicrobial assays can also be considered as possible candidates for additional rounds of assessment and redesign.…”

Section: Understanding Antibiotic Permeation Through Bacterial Nanoporesmentioning

confidence: 99%

“…25 was studied in computational investigations that indicated the role of the interactions of the amine group with the negatively charged residues of the constriction loop. 28 Certainly, molecules that have been screened as potent inhibitors in in vitro binding assays but have failed in antimicrobial assays can also be considered as possible candidates for additional rounds of assessment and redesign. The eNTRy criteria may be incorporated at various phases of drug development, for instance, during the hit-to-lead stage, in the lead optimization, or within the virtual drug design workflow.…”

Section: ■ Introductionmentioning

confidence: 99%

Atomistic Simulation of Molecules Interacting with Biological Nanopores: From Current Understanding to Future Directions

2022

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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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Rationalizing the generation of broad spectrum antibiotics with the addition of a positive charge

Abstract: Antibiotic resistance of Gram-negative bacteria is largely attributed to the low permeability of their outer membrane (OM). Recently, we disclosed the eNTRy rules, a key lesson of which is that...

Cited by 20 publications

References 95 publications

Conformational Dynamics of Loop L3 in OmpF: Implications toward Antibiotic Translocation and Voltage Gating

Conformational Dynamics of Loop L3 in OmpF: Implications toward Antibiotic Translocation and Voltage Gating

AB-DB: Force-Field parameters, MD trajectories, QM-based data, and Descriptors of Antimicrobials

Atomistic Simulation of Molecules Interacting with Biological Nanopores: From Current Understanding to Future Directions

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