A novel strategy to screen inhibitors of multiple aminoglycoside-modifying enzymes with ultra-high performance liquid chromatography-quadrupole-time-of-flight mass spectrometry

Zhu, Li; Liu, Ruonan; Liu, Tangrong; Zou, Xuan; Xu, Zhe; Guan, Huashi

doi:10.1016/j.jpba.2018.11.021

Cited by 7 publications

(8 citation statements)

References 32 publications

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“…24 A modern chromatography-coupled mass spectrometry method was recently developed for discovery of AMEs. 25 A major mode of resistance to an antibiotic is a mutation in its target. Such mutations significantly weaken the binding of this antibiotic to its target while not substantially affecting a function of this target.…”

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confidence: 99%

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Probing the Robustness of Inhibitors of Tuberculosis Aminoglycoside Resistance Enzyme Eis by Mutagenesis

et al. 2019

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Each year, millions of people worldwide contract tuberculosis (TB), the deadliest infection. The spread of infections with drug-resistant strains of Mycobacterium tuberculosis (Mtb) that are refractory to treatment poses a major global challenge. A major cause of resistance to antitubercular drugs of last resort, aminoglycosides, is overexpression of the Eis (enhanced intracellular survival) enzyme of Mtb, which inactivates aminoglycosides by acetylating them. We showed previously that this inactivation of aminoglycosides could be overcome by our recently reported Eis inhibitors that are currently in development as potential aminoglycoside adjunctive therapeutics against drug-resistant TB. To interrogate the robustness of the Eis inhibitors, we investigated the enzymatic activity of Eis and its inhibition by Eis inhibitors from three different structural families for nine single-residue mutants of Eis, including those found in the clinic. Three engineered mutations of the substrate binding site, D26A, W36A, and F84A, abolished inhibitor binding while compromising Eis enzymatic activity 2-to 3-fold. All other Eis mutants, including clinically observed ones, were potently inhibited by at least one inhibitor. This study helps position us one step ahead of Mtb resistance to Eis inhibitors as they are being developed for TB therapy.

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confidence: 99%

“…Another example of an AME inhibitor is streptidine, which competes with the aminoglycoside streptomycin for binding aminoglycoside nucleotidyltransferase ANT(6), overcoming ANT(6)-mediated resistance to streptomycin of Escherichia coli overexpressing ANT(6) . A modern chromatography-coupled mass spectrometry method was recently developed for discovery of AMEs …”

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Probing the Robustness of Inhibitors of Tuberculosis Aminoglycoside Resistance Enzyme Eis by Mutagenesis

et al. 2019

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“…Indeed, such inhibitors have been used to maintain the therapeutic efficacy of drugs (aminopenicillins, cephalosporins, carbapenems), even though resistance to the inhibitor-drug combination might occur. Research on inhibitors for other drug-modifying proteins, such as aminoglycoside-modifying enzymes, is ongoing (Zhu, et al, 2019). Another approach is to inhibit processes leading to resistance, e.g.…”

Section: Population Level Analysis Imentioning

confidence: 99%

Antibiotic resistance: turning evolutionary principles into clinical reality

Andersson

Balaban

Baquero

et al. 2020

FEMS Microbiology Reviews

186

118

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Antibiotic resistance is one of the major challenges facing modern medicine worldwide. The past few decades have witnessed rapid progress in our understanding of the multiple factors that affect the emergence and spread of antibiotic resistance at the population level and the level of the individual patient. However, the process of translating this progress into health policy and clinical practice has been slow. Here, we attempt to consolidate current knowledge about the evolution and ecology of antibiotic resistance into a roadmap for future research as well as clinical and environmental control of antibiotic resistance. At the population level, we examine emergence, transmission and dissemination of antibiotic resistance, and at the patient level, we examine adaptation involving bacterial physiology and host resilience. Finally, we describe new approaches and technologies for improving diagnosis and treatment and minimizing the spread of resistance.

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“…aureus that potentiates amikacin activity in vitro . More recently, a small-scale screen identified additional inhibitors of AAC(6′)-APH(2″) enzymes . As a target class though, aminoglycoside-modifying enzymes are not as economically attractive as β-lactamases due to their inability to breathe new life into multiple broad-spectrum antibiotics.…”

Section: The Quest For Resistance Enzyme Inhibitors That Breathe New ...mentioning

confidence: 99%

“…125 More recently, a small-scale screen identified additional inhibitors of AAC(6′)-APH(2″) enzymes. 126 As a target class though, aminoglycoside-modifying enzymes are not as economically attractive as β-lactamases due to their inability to breathe new life into multiple broad-spectrum antibiotics. An alternative approach to rejuvenating the effectiveness of aminoglycosides has already been taken with plazomicin (52), a semisynthetic aminoglycoside that is not a substrate for most AMEs.…”

Section: Inhibitors That Breathe New Life Into Old Antibiotics Must C...mentioning

confidence: 99%

Prospects for Antibacterial Discovery and Development

et al. 2021

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The rising prevalence of multidrug-resistant bacteria is an urgent health crisis that can only be countered through renewed investment in the discovery and development of antibiotics. There is no panacea for the antibacterial resistance crisis; instead, a multifaceted approach is called for. In this Perspective we make the case that, in the face of evolving clinical needs and enabling technologies, numerous validated antibacterial targets and associated lead molecules deserve a second look. At the same time, many worthy targets lack good leads despite harboring druggable active sites. Creative and inspired techniques buoy discovery efforts; while soil screening efforts frequently lead to antibiotic rediscovery, researchers have found success searching for new antibiotic leads by studying underexplored ecological niches or by leveraging the abundance of available data from genome mining efforts. The judicious use of “polypharmacology” (i.e., the ability of a drug to alter the activities of multiple targets) can also provide new opportunities, as can the continued search for inhibitors of resistance enzymes with the capacity to breathe new life into old antibiotics. We conclude by highlighting available pharmacoeconomic models for antibacterial discovery and development while making the case for new ones.

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A novel strategy to screen inhibitors of multiple aminoglycoside-modifying enzymes with ultra-high performance liquid chromatography-quadrupole-time-of-flight mass spectrometry

Cited by 7 publications

References 32 publications

Probing the Robustness of Inhibitors of Tuberculosis Aminoglycoside Resistance Enzyme Eis by Mutagenesis

Probing the Robustness of Inhibitors of Tuberculosis Aminoglycoside Resistance Enzyme Eis by Mutagenesis

Antibiotic resistance: turning evolutionary principles into clinical reality

Prospects for Antibacterial Discovery and Development

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