scholarly journals Reaction Kinetic Models of Antibiotic Heteroresistance

2019 ◽  
Vol 20 (16) ◽  
pp. 3965
Author(s):  
Antal Martinecz ◽  
Fabrizio Clarelli ◽  
Sören Abel ◽  
Pia Abel zur Wiesch

Bacterial heteroresistance (i.e., the co-existence of several subpopulations with different antibiotic susceptibilities) can delay the clearance of bacteria even with long antibiotic exposure. Some proposed mechanisms have been successfully described with mathematical models of drug-target binding where the mechanism’s downstream of drug-target binding are not explicitly modeled and subsumed in an empirical function, connecting target occupancy to antibiotic action. However, with current approaches it is difficult to model mechanisms that involve multi-step reactions that lead to bacterial killing. Here, we have a dual aim: first, to establish pharmacodynamic models that include multi-step reaction pathways, and second, to model heteroresistance and investigate which molecular heterogeneities can lead to delayed bacterial killing. We show that simulations based on Gillespie algorithms, which have been employed to model reaction kinetics for decades, can be useful tools to model antibiotic action via multi-step reactions. We highlight the strengths and weaknesses of current models and Gillespie simulations. Finally, we show that in our models, slight normally distributed variances in the rates of any event leading to bacterial death can (depending on parameter choices) lead to delayed bacterial killing (i.e., heteroresistance). This means that a slowly declining residual bacterial population due to heteroresistance is most likely the default scenario and should be taken into account when planning treatment length.

2019 ◽  
Vol 25 (31) ◽  
pp. 3339-3349 ◽  
Author(s):  
Indrani Bera ◽  
Pavan V. Payghan

Background: Traditional drug discovery is a lengthy process which involves a huge amount of resources. Modern-day drug discovers various multidisciplinary approaches amongst which, computational ligand and structure-based drug designing methods contribute significantly. Structure-based drug designing techniques require the knowledge of structural information of drug target and drug-target complexes. Proper understanding of drug-target binding requires the flexibility of both ligand and receptor to be incorporated. Molecular docking refers to the static picture of the drug-target complex(es). Molecular dynamics, on the other hand, introduces flexibility to understand the drug binding process. Objective: The aim of the present study is to provide a systematic review on the usage of molecular dynamics simulations to aid the process of structure-based drug design. Method: This review discussed findings from various research articles and review papers on the use of molecular dynamics in drug discovery. All efforts highlight the practical grounds for which molecular dynamics simulations are used in drug designing program. In summary, various aspects of the use of molecular dynamics simulations that underline the basis of studying drug-target complexes were thoroughly explained. Results: This review is the result of reviewing more than a hundred papers. It summarizes various problems that use molecular dynamics simulations. Conclusion: The findings of this review highlight how molecular dynamics simulations have been successfully implemented to study the structure-function details of specific drug-target complexes. It also identifies the key areas such as stability of drug-target complexes, ligand binding kinetics and identification of allosteric sites which have been elucidated using molecular dynamics simulations.


2019 ◽  
Vol 7 ◽  
Author(s):  
Maha Thafar ◽  
Arwa Bin Raies ◽  
Somayah Albaradei ◽  
Magbubah Essack ◽  
Vladimir B. Bajic

2020 ◽  
Vol 16 (8) ◽  
pp. e1008106
Author(s):  
Fabrizio Clarelli ◽  
Adam Palmer ◽  
Bhupender Singh ◽  
Merete Storflor ◽  
Silje Lauksund ◽  
...  

2021 ◽  
Author(s):  
Elany Barbosa Da Silva ◽  
Vandna Sharma ◽  
Lilian Hernandez-Alvarez ◽  
Arthur H Tang ◽  
Alexander Stoye ◽  
...  

Gallinamide A, a metabolite of the marine cyanobacterium Schizothrix sp., selectively inhibits cathepsin L-like cysteine proteases. We evaluated potency of gallinamide A and 23 synthetic analogs against intracellular Trypanosoma cruzi amastigotes and the cysteine protease, cruzain. We determined the co-crystal structures of cruzain with gallinamide A and two synthetic analogs at ~2Å. SAR data revealed that the N-terminal end of gallinamide A is loosely bound and weakly contributes in drug-target interactions. At the C-terminus, the intramolecular π-π stacking interactions between the aromatic substituents at P1 ′ and P1 restrict the bioactive conformation of the inhibitors, thus minimizing the entropic loss associated with target binding. Molecular dynamics simulations showed that in the absence of an aromatic group at P1, the substituent at P1′ interacts with tryptophan-184. The P1-P1′ interactions had no effect on anti-cruzain activity whereas anti-T. cruzi potency increased by ~5-fold, likely due to an increase in solubility/permeability of the analogs.


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