Compounds that select against the tetracycline-resistance efflux pump

Abstract

We developed a competition-based screening strategy to identify compounds that invert the selective advantage of antibiotic resistance. Using our assay, we screened over 19,000 compounds for the ability to select against the TetA tetracycline resistance efflux pump in E. coli and identified two hits: β-thujaplicin and disulfiram. Treating a tetracycline resistant population with β-thujaplicin selects for loss of the resistance gene, enabling an effective second-phase treatment with doxycycline.

Time-programmable drug dosing allows the manipulation, suppression and reversal of antibiotic drug resistance in vitro

“…Recent studies indicate that it is possible to revert bacterial resistance to a single antibiotic by using antibiotics in a temporally segregated manner102952. Although collateral sensitivity has been known for more than 60 years53, the importance of this phenomenon for suppressing the development of drug resistance was not well recognized until recently54, which may account for failed clinical or animal studies on antibiotic cycling.…”

Next-generation approaches to understand and combat the antibiotic resistome

“…A recent highlight in the search for selection-inverting compounds involved a screen of nearly 20,000 small molecules for compounds that select against the tetracycline efflux pump TetA. This screen identified two candidates that successfully selected for the loss of the tetA gene 70 . Perhaps more important are drugs under development and in early-phase testing that target AcrA–AcrB–TolC efflux complexes in Gram-negative bacteria.…”

Suppressive drug combinations and their potential to combat antibiotic resistance

“…In certain cases, major pathogens such as extensively drug resistant tuberculosis (XDR-TB), have developed resistance to virtually every effective antibiotic regime. 4 To combat this impending crisis, researchers have focused on identifying antibiotic classes with novel cellular and metabolic targets, 5 modifications to existing drugs that restore effectiveness against resistant bacteria, 6 and co-administered chemical agents that disable specific drug resistance mechanisms, 7, 8 increase antibiotic bioavailability, 9 or decrease toxicity of high dosages to the patient. 10 Researchers and clinicians have additionally taken into account physiological changes in patients that affect antibiotic concentrations and bacterial susceptibility (sensitivity) in order to maximize the effectiveness of antibiotics through individualized antibiotic dosing.…”

“…15 For instance, policy controls on antibiotic use in agriculture and their periodic removal from clinical use are aimed at reducing unnecessary selection for resistance, 16 while screens for non-antibiotic compounds that target particular resistance mechanisms aim to eliminate them by increasing the cost of their carriage. 8, 17 …”