The relationship between target-class and the physicochemical properties of antibacterial drugs

Mugumbate, Grace; Overington, John P.

doi:10.1016/j.bmc.2015.04.063

Cited by 45 publications

(48 citation statements)

References 30 publications

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“…We hypothesized that selecting small and hydrophilic inhibitors (Lipinski's rules) would facilitate both entry into bacterial cells and future drug development efforts (Lipinski et al, 1997). Although effective antibiotics vary greatly in these parameters, most bacterial protein targeting drugs obey these guidelines (Mugumbate & Overington, 2015). Our IPAs could substantially inhibit growth of a non-pathogenic mycobacterium (Msmeg), a pathogenic mycobacterium (Mab), and a pathogenic non-mycobacterial actinobacteria (Nast) at micromolar levels when potentiated by a βlactam (Fig.…”

Section: Discussionmentioning

confidence: 99%

Repurposed kinase inhibitors and β-lactams as a novel therapy for antibiotic resistant bacteria

Wlodarchak

Teachout

Procknow

et al. 2017

Preprint

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Antibiotic resistant bacteria are an increasing global problem, and pathogenic actinomycetes and firmicutes are particularly challenging obstacles. These pathogens share several eukaryotic-like kinases that present antibiotic development opportunities. We used computational modelling to identify human kinase inhibitors that could be repurposed towards bacteria as part of a novel combination therapy. The computational model suggested a family of inhibitors, the imidazopyridine aminofurazans (IPAs), bind PknB with high affinity. We found that these inhibitors biochemically inhibit PknB, with potency roughly following the predicted models. A novel x-ray structure confirmed that the inhibitors bind as predicted and made favorable protein contacts with the target. These inhibitors also have antimicrobial activity towards Mycobacteria and Nocardia, and normally ineffective β-lactams can potentiate IPAs to more efficiently inhibit growth of these pathogens. Collectively, our data show that in silico modeling can be used as a tool to discover promising drug leads, and the inhibitors we discovered can synergize with clinically relevant antibiotics to restore their efficacy against bacteria with limited treatment options.

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Section: Discussionmentioning

confidence: 99%

Repurposed kinase inhibitors and β-lactams as a novel therapy for antibiotic resistant bacteria

Wlodarchak

Teachout

Procknow

et al. 2017

Preprint

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“…Additionally, the two most important applications of physicochemical parameters to assess drug-likeness are the well-known Lipinski's rule of five (RO5) [54] and the Golden Triangle rule [55] that were originally proposed by taking into account the properties of successful drug compounds of that time. The application of these rules to true therapeutic targets has been extensively reported in literature [81][82][83][84][85]. However, here we have monitored the RO5 and Golden Triangle violations for the inhibitors of antitargets, the cytochrome P450 family of enzymes.…”

Section: Physicochemical Propertiesmentioning

confidence: 99%

Exploring the Chemical Space of Cytochrome P450 Inhibitors Using Integrated Physicochemical Parameters, Drug Efficiency Metrics and Decision Tree Models

Kiani

Jabeen

2019

Computation

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The cytochrome P450s (CYPs) play a central role in the metabolism of various endogenous and exogenous compounds including drugs. CYPs are vulnerable to inhibition and induction which can lead to adverse drug reactions. Therefore, insights into the underlying mechanism of CYP450 inhibition and the estimation of overall CYP inhibitor properties might serve as valuable tools during the early phases of drug discovery. Herein, we present a large data set of inhibitors against five major metabolic CYPs (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) for the evaluation of important physicochemical properties and ligand efficiency metrics to define property trends across various activity levels (active, efficient and inactive). Decision tree models for CYP inhibition were developed with an accuracy >90% for both the training set and 10-folds cross validation. Overall, molecular weight (MW), hydrogen bond acceptors/donors (HBA/HBD) and lipophilicity (clogP/logPo/w) represent important physicochemical descriptors for CYP450 inhibitors. However, highly efficient CYP inhibitors show mean MW, HBA, HBD and logP values between 294.18–482.40,5.0–8.2,1–7.29 and 1.68–2.57, respectively. Our results might help in optimization of toxicological profiles associated with new chemical entities (NCEs), through a better understanding of inhibitor properties leading to CYP-mediated interactions.

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“…79 Aligning yet further the libraries to coincide with the different antibacterial sub-classes (such as attention to the requirements for optimal inhibition of cell wall targets compared to the ribosome as a target) may improve success. 80 Nonetheless—and notwithstanding the reality that successful antibacterial discovery requires more than optimization of the physicochemical properties of the chemical library 81 —there are antibacterials waiting to be found in chemical libraries. For example, the interplay of library screening, synthesis, and the use of reverse genomics identified the spiropyrimidinetrione inhibitors of the bacterial topoisomerases.…”

Section: Endless Antibiotics: a Chemical Perspectivementioning

confidence: 99%

Endless resistance. Endless antibiotics?

Fisher

Mobashery

2016

Med. Chem. Commun.

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The practice of medicine was profoundly transformed by the introduction of the antibiotics (compounds isolated from Nature) and the antibacterials (compounds prepared by synthesis) for the control of bacterial infection. As a result of the extraordinary success of these compounds over decades of time, a timeless biological activity for these compounds has been presumed. This presumption is no longer. The inexorable acquisition of resistance mechanisms by bacteria is retransforming medical practice. Credible answers to this dilemma are far better recognized than they are being implemented. In this perspective we examine (and in key respects, reiterate) the chemical and biological strategies being used to address the challenge of bacterial resistance.

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The relationship between target-class and the physicochemical properties of antibacterial drugs

Abstract: Graphical abstract

Cited by 45 publications

References 30 publications

Repurposed kinase inhibitors and β-lactams as a novel therapy for antibiotic resistant bacteria

Repurposed kinase inhibitors and β-lactams as a novel therapy for antibiotic resistant bacteria

Exploring the Chemical Space of Cytochrome P450 Inhibitors Using Integrated Physicochemical Parameters, Drug Efficiency Metrics and Decision Tree Models

Endless resistance. Endless antibiotics?

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