Reversal of Tetracycline Resistance Mediated by Different Bacterial Tetracycline Resistance Determinants by an Inhibitor of the Tet(B) Antiport Protein

Abstract

Active efflux is a useful strategy by which bacteria evade growth inhibition by antibiotics. Certain semisynthetic tetracycline (TC) analogs, substituted at the 13th carbon at C-6 on ring C of the TC molecule, blocked TC efflux as revealed in everted membrane vesicles from class B TC-resistant (Tcr) Escherichia coli (M. L. Nelson, B. H. Park, J. S. Andrews, V. A. Georgian, R. C. Thomas, and S. B. Levy, J. Med. Chem. 36:370–377, 1993). A representative C-13-substituted analog, 13-cyclopentylthio-5-OH-TC (13-CPTC), was shown to competitively inhibit TC translocation by the Tet(B) protein, blocking the uptake of TC into vesicles and therefore the efflux of TC from whole cells. Against Tcr E. coli, 13-CPTC, when used in combination with doxycycline, produced synergistic inhibition of growth. 13-CPTC was shown to increase the uptake of [3H]TC into the resistant cells. 13-CPTC alone was a potent growth inhibitor against TC-susceptible (Tcs) and Tcr Staphylococcus aureus and enterococci specifying class K or class L efflux-dependent TC resistance mechanisms or, unexpectedly, the class M ribosomal protection mechanism. These findings indicate that derivatives of TC, identified by their ability to block the Tet(B) efflux protein, can restore TC activity against Tcr bacteria bearing either of the two known resistance mechanisms. Blocking drug efflux and increasing intracellular drug concentrations constitute an effective approach to reversing TC resistance and may be generally applicable to other antibiotics rendered ineffective by efflux proteins.

Extremely High Frequency Electromagnetic Radiation Enforces Bacterial Effects of Inhibitors and Antibiotics

“…1 and 2 [10,14] and these antibiotics [32][33][34][35][36] on bacteria occurs through membranous mechanisms: changes in the properties of membrane proteins and namely in the F 0 F 1 -ATPase can mediate such action. Differences in membrane proteome [41], membrane permeabilization, discharging protonmotive force [32,36], which is generated by the F 0 F 1 -ATPase under fermentation conditions (for review, see [31]), disturbances in H + , K + and Na + transport [35], alterations in appropriate transport systems, and lowering ATP level [32,34] increase sensitivity to antibiotics. In addition, alteration in DNA gyrase and other changes in gene expression or protein synthesis are also important in sensitivity to antibiotics (for review, see [42]).…”

“…This might be due to the role a membrane plays in bactericidal effects of tetracycline and chloramphenicol [32][33][34][35][36]. These antibiotics were effective in decreasing E. coli K12(k) specific growth rate: the effects were obtained in a concentration-dependent manner (for 2-10 lM, not shown) as determined before by different groups [33,37].…”

Clonal dissemination of a single Shigella sonnei strain among Iranian children during Fall 2012 in Tehran, I.R. Iran

“…This high resistance is due to the acquisition and transfer of resistance determinants via horizontal transfer of the resistance plasmids, transposons and integrons that may lead to higher fatality rates (Spicknall et al, 2013). Tetracycline which is a broad-spectrum antibiotic that can inhibit protein synthesis in a wide range of Gram positive and Gram negative organisms (Nelson and Levy, 1999;Nelson et al, 1993).Currently, the use of this antibiotic in the treatment of human infections and prevention of bacterial infections in agriculture and livestock increases the rate of resistance to this class of antimicrobial agents (Chopra and Roberts, 2001).One of the major mechanisms involved in the resistance to tetracycline is the efflux pump systems including tet(A), (B), (C), (D), (E), (G), (I), (M) and (K) genes, the first four genes are more widespread in Gram negative bacteria including Shigella spp. (Roberts, 1996).…”

Bacterial Efflux Pumps Involved in Multidrug Resistance and their Inhibitors: Rejuvinating the Antimicrobial Chemotherapy

“…Analogs of tetracyclines, quinolones and aminoglycosides have been studied and patented so far. Tetracycline analogs have been designed to increase the susceptibility of S. aureus against tetracyclines [131][132][133][134][135]. Such compounds have now been tested with several pathogens and several antibiotics [132][133][134].…”