A Small Molecule Discrimination Map of the Antibiotic Resistance Kinome

Shakya, Tushar; Stogios, P.J.; Waglechner, Nicholas; Evdokimova, E.; Ejim, Linda; Blanchard, Jan; McArthur, Andrew G.; Savchenko, Alexei; Wright, Gerard D.

doi:10.1016/j.chembiol.2011.10.018

Cited by 73 publications

(78 citation statements)

References 56 publications

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“…353 The notion of directly inhibiting resistance elements, thereby rescuing antibiotic activity, is not confi ned to the β-lactam antibiotics. Eff orts to block aminoglycoside-inactivating enzymes 354 and antibiotic effl ux pumps 355 have also proven eff ective in vitro, though none have progressed to clinical trials yet.…”

Section: Adjuvantsmentioning

confidence: 99%

Antibiotic resistance—the need for global solutions

Laxminarayan

Dusé

Wattal

et al. 2013

The Lancet Infectious Diseases

3,601

2,602

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The causes of antibiotic resistance are complex and include human behaviour at many levels of society; the consequences aff ect everybody in the world. Similarities with climate change are evident. Many eff orts have been made to describe the many diff erent facets of antibiotic resistance and the interventions needed to meet the challenge. However, coordinated action is largely absent, especially at the political level, both nationally and internationally. Antibiotics paved the way for unprecedented medical and societal developments, and are today indispensible in all health systems. Achievements in modern medicine, such as major surgery, organ transplantation, treatment of preterm babies, and cancer chemotherapy, which we today take for granted, would not be possible without access to eff ective treatment for bacterial infections. Within just a few years, we might be faced with dire setbacks, medically, socially, and economically, unless real and unprecedented global coordinated actions are immediately taken. Here, we describe the global situation of antibiotic resistance, its major causes and consequences, and identify key areas in which action is urgently needed.

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Section: Adjuvantsmentioning

confidence: 99%

Antibiotic resistance—the need for global solutions

Laxminarayan

Dusé

Wattal

et al. 2013

The Lancet Infectious Diseases

3,601

2,602

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“…Efforts to overexpress Rgt1438 in E. coli failed despite numerous attempts. We therefore turned to protein expression in the actinomycete Rhodococcus erythropolis, which we had previously found useful in generating soluble and active protein expressed from high-GCcontent genes (30,34,40). Using this system, soluble and active N-terminal His 6 -tagged Rgt1438 was successfully overexpressed and purified to homogeneity using a two-step chromatographic protocol (see Fig.…”

Section: Figmentioning

confidence: 99%

Characterization of a Rifampin-Inactivating Glycosyltransferase from a Screen of Environmental Actinomycetes

Spanogiannopoulos

Thaker

Koteva

et al. 2012

Antimicrob Agents Chemother

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Identifying and understanding the collection of all antibiotic resistance determinants presented in the global microbiota, the antibiotic resistome, provides insight into the evolution of antibiotic resistance and critical information for the development of future antimicrobials. The rifamycins are broad-spectrum antibiotics that target bacterial transcription by inhibition of RNA polymerase. Although mutational alteration of the drug target is the predominant mechanism of resistance to this family of antibiotics in the clinic, a number of diverse inactivation mechanisms have also been reported. In this report, we investigate a subset of environmental rifampin-resistant actinomycete isolates and identify a diverse collection of rifampin inactivation mechanisms. We describe a single isolate, WAC1438, capable of inactivating rifampin by glycosylation. A draft genome sequence of WAC1438 (most closely related to Streptomyces speibonae, according to a 16S rRNA gene comparison) was assembled, and the associated rifampin glycosyltransferase open reading frame, rgt1438, was identified. The role of rgt1438 in rifampin resistance was confirmed by its disruption in the bacterial chromosome, resulting in a loss of antibiotic inactivation and a 4-fold decrease in MIC. Interestingly, examination of the RNA polymerase ␤-subunit sequence of WAC1438 suggests that it harbors a resistant target and thus possesses dual mechanisms of rifamycin resistance. Using an in vitro assay with purified enzyme, Rgt1438 could inactivate a variety of rifamycin antibiotics with comparable steady-state kinetics constants. Our results identify rgt1438 as a rifampin resistance determinant from WAC1438 capable of inactivating an assortment of rifamycins, adding a new element to the rifampin resistome.

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“…In this study, GW5074 demonstrated broad specificity against antibiotic kinases that play an important role in developing resistance in bacteria [52]. We wanted to test this theory and assess the ability of this compound to act synergistically with known antibiotics, like aminoglycosides, in killing S. aureus.…”

Section: Discussionmentioning

confidence: 99%

Raf-Kinase Inhibitor Gw5074 Shows Antibacterial Activity Against Methicillin-Resistant Staphylococcus Aureus and Potentiates the Activity of Gentamicin

et al. 2016

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Aim:Increasing antimicrobial resistance has compromised the effectiveness of many antibiotics, including those used to treat staphylococcal infections like methicillinresistant Staphylococcus aureus. The development of combination therapies, where antimicrobial agents are used with compounds that inhibit resistance pathways is a promising strategy. Results/methodology: The Raf kinase inhibitor GW5074 exhibited selective in vitro activity against Gram-positive bacteria, including clinical isolates of S. aureus with a minimum inhibitory concentration (MIC) of 2-8 μg/ml. GW5074 was effective in vivo in the Galleria mellonella infection model. The compound showed synergy with gentamicin by lowering MIC by fourfold, compared with gentamicin MIC alone. Conclusion: This work demonstrates the antimicrobial properties of GW5074 and supports further investigation of the kinase inhibitors as antibiotic adjuvants.

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A Small Molecule Discrimination Map of the Antibiotic Resistance Kinome

Cited by 73 publications

References 56 publications

Antibiotic resistance—the need for global solutions

Antibiotic resistance—the need for global solutions

Characterization of a Rifampin-Inactivating Glycosyltransferase from a Screen of Environmental Actinomycetes

Raf-Kinase Inhibitor Gw5074 Shows Antibacterial Activity Against Methicillin-Resistant Staphylococcus Aureus and Potentiates the Activity of Gentamicin

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