Illicit Transport via Dipeptide Transporter Dpp is Irrelevant to the Efficacy of Negamycin in Mouse Thigh Models of Escherichia coli Infection.
Negamycin is a hydrophilic antimicrobial translation inhibitor that crosses the lipophilic inner membrane of Escherichia coli via at least two transport routes to reach its intracellular target. In a minimal salts medium, negamycin's peptidic nature allows illicit entry via a high-affinity route by hijacking the Dpp dipeptide transporter. Transport via a second, low-affinity route is energetically driven by the membrane potential, seemingly without the direct involvement of a transport protein. In mouse thigh models of E. coli infection, no evidence for Dpp-mediated transport of negamycin was found. The implication is that for the design of new negamycin-based analogs, the physicochemical properties required for cell entry via the low-affinity route need to be retained to achieve clinical success in the treatment of infectious diseases. Furthermore, clinical resistance to such analogs due to mutations affecting their ribosomal target or transport is expected to be rare and similar to that of aminoglycosides.
Departments of Chemistry, ‡Biosciences, and §Drug Metabolism and Pharmacokinetics, Infection Innovative Medicines Unit , AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
David C
DC
McKinney
Departments of Chemistry, ‡Biosciences, and §Drug Metabolism and Pharmacokinetics, Infection Innovative Medicines Unit , AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
Natascha
N
Bezdenejnih-Snyder
Departments of Chemistry, ‡Biosciences, and §Drug Metabolism and Pharmacokinetics, Infection Innovative Medicines Unit , AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
Krista
K
Farrington
Departments of Chemistry, ‡Biosciences, and §Drug Metabolism and Pharmacokinetics, Infection Innovative Medicines Unit , AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
Jian
J
Guo
Departments of Chemistry, ‡Biosciences, and §Drug Metabolism and Pharmacokinetics, Infection Innovative Medicines Unit , AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
Robert E
RE
McLaughlin
Departments of Chemistry, ‡Biosciences, and §Drug Metabolism and Pharmacokinetics, Infection Innovative Medicines Unit , AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
Anatoly M
AM
Ruvinsky
Departments of Chemistry, ‡Biosciences, and §Drug Metabolism and Pharmacokinetics, Infection Innovative Medicines Unit , AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
Renu
R
Singh
Departments of Chemistry, ‡Biosciences, and §Drug Metabolism and Pharmacokinetics, Infection Innovative Medicines Unit , AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
Gregory S
GS
Basarab
Departments of Chemistry, ‡Biosciences, and §Drug Metabolism and Pharmacokinetics, Infection Innovative Medicines Unit , AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
Sridhar
S
Narayan
Departments of Chemistry, ‡Biosciences, and §Drug Metabolism and Pharmacokinetics, Infection Innovative Medicines Unit , AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
Ed T
ET
Buurman
aminoglycosides; dipeptide; efficacy; membrane potential; negamycin; ribosome