The bacterial outer membrane as a drug barrier

doi:10.1016/S0966-842X(97)81773-8

Trends in Microbiology

Volume 5, Issue 1, January 1997, Pages 37-42

https://doi.org/10.1016/S0966-842X(97)81773-8 Get rights and content

The outer membranes of Gram-negative bacteria constitute a semi-permeable barrier, as indicated by the corresponding alterations in outer membrane permeability and in antibiotic susceptibility resulting from mutation or polycation action. Restricted outer membrane permeability works in synergy with co-determinant resistance mechanisms, such as the periplasmic enzyme β-lactamase or active efflux mechanisms, bringing about antibiotic resistance.

References (26)

LewisK.
Trends Biochem. Sci.
(1994)
MaD.
Trends Microbiol.
(1994)
HancockR.E.W. et al.
NikaidoH.
Biochim. Biophys. Acta
(1976)
HancockR.E.W. et al.
Clin. Microbiol. Infect.
(1996)
HancockR.E.W. et al.
Adv. Microb. Physiol.
(1995)
JacobyG.A.J.
Trends Microbiol.
(1994)
NikaidoH. et al.
Microbiol. Rev.
(1985)
HancockR.E.W.
J. Bacteriol.
(1987)
CowanS.W.
Nature
(1992)

WeissM.S.

Science

(1991)

SchirmerT.

Science

(1995)

HancockR.E.W. et al.

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Trends in Microbiology

ReviewThe bacterial outer membrane as a drug barrier

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Clin. Microbiol. Infect.

Adv. Microb. Physiol.

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Review
The bacterial outer membrane as a drug barrier