Molecular Determinants of AcrB-Mediated Bacterial Efflux Implications for Drug Discovery

Manchester, John I.; Buurman, Ed T.; Bisacchi, Gregory S.; McLaughlin, Robert E.

doi:10.1021/jm201275d

Cited by 46 publications

(53 citation statements)

References 47 publications

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“…It seems that compounds using different pathways to the cytoplasm may fall into different physicochemical regions (defined by more extensive sets of descriptors, some likely structural) -in line with the proposal that the characteristics of the compounds are related to the barriers they must pass as specifically noted by in references 12,63 .…”

Section: Binning Compounds By Barriers To Entrysupporting

confidence: 57%

“…Recognition of the multiple possible mechanism that GN compounds use to attain residence in the cytoplasm has no doubt influenced the thinking of many who have tried to come up with rules for entry. For example, Manchester, et al 12 note that there are no simple rules for GN entry, but recognize examples of "privileged compounds" that have various routes of barrier passage or other attributes that might be considered as bins. All compounds in this bin with CLogD <-2.9 are tetracyclines.…”

Section: Binning Compounds By Barriers To Entrymentioning

confidence: 99%

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A Gestalt approach to Gram-negative entry

Silver¹

2016

Bioorganic & Medicinal Chemistry

152

193

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Section: Binning Compounds By Barriers To Entrysupporting

confidence: 57%

Section: Binning Compounds By Barriers To Entrymentioning

confidence: 99%

A Gestalt approach to Gram-negative entry

Silver¹

2016

Bioorganic & Medicinal Chemistry

152

193

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“…These studies complement the activity-based approaches to identify physicochemical properties that facilitate efflux of compounds. 109 …”

Section: Approaches To Bypass or Break The Permeability Barriermentioning

confidence: 99%

Permeability Barrier of Gram-Negative Cell Envelopes and Approaches To Bypass It

2015

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Gram-negative bacteria are intrinsically resistant to many antibiotics. Species that have acquired multidrug resistance and cause infections that are effectively untreatable present a serious threat to public health. The problem is broadly recognized and tackled at both the fundamental and applied levels. This paper summarizes current advances in understanding the molecular bases of the low permeability barrier of Gram-negative pathogens, which is the major obstacle in discovery and development of antibiotics effective against such pathogens. Gaps in knowledge and specific strategies to break this barrier and to achieve potent activities against difficult Gram-negative bacteria are also discussed.

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“…Mutant strains with defects in the biosynthesis of LPS are also hypersusceptible to antibiotics, but as in the case of polymyxin, these modifications increase cell surface hydrophobicity and facilitate predominantly the penetration of hydrophobic antibiotics (17). To address the penetration of hydrophilic compounds, bacterial strains and species producing mutant or larger porins are used (18). However, such porins are still highly selective according to the properties of the compounds.…”

mentioning

confidence: 99%

Breaking the Permeability Barrier of Escherichia coli by Controlled Hyperporination of the Outer Membrane

Krishnamoorthy

Wolloscheck

Weeks

et al. 2016

Antimicrob Agents Chemother

114

186

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In Gram-negative bacteria, a synergistic relationship between slow passive uptake of antibiotics across the outer membrane and active efflux transporters creates a permeability barrier, which efficiently reduces the effective concentrations of antibiotics in cells and, hence, their activities. To analyze the relative contributions of active efflux and the passive barrier to the activities of antibiotics, we constructed Escherichia coli strains with controllable permeability of the outer membrane. The strains expressed a large pore that does not discriminate between compounds on the basis of their hydrophilicity and sensitizes cells to a variety of antibacterial agents. We found that the efficacies of antibiotics in these strains were specifically affected by either active efflux or slow uptake, or both, and reflect differences in the properties of the outer membrane barrier, the repertoire of efflux pumps, and the inhibitory activities of antibiotics. Our results identify antibiotics which are the best candidates for the potentiation of activities through efflux inhibition and permeabilization of the outer membrane.

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Molecular Determinants of AcrB-Mediated Bacterial Efflux Implications for Drug Discovery

Cited by 46 publications

References 47 publications

A Gestalt approach to Gram-negative entry

A Gestalt approach to Gram-negative entry

Permeability Barrier of Gram-Negative Cell Envelopes and Approaches To Bypass It

Breaking the Permeability Barrier of Escherichia coli by Controlled Hyperporination of the Outer Membrane

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