Multidrug evolutionary strategies to reverse antibiotic resistance

Abstract

Antibiotic treatment has two conflicting effects: the desired, immediate effect of inhibiting bacterial growth and the undesired, long-term effect of promoting the evolution of resistance. Although these contrasting outcomes seem inextricably linked, recent work has revealed several ways by which antibiotics can be combined to inhibit bacterial growth while, counterintuitively, selecting against resistant mutants. Decoupling treatment efficacy from the risk of resistance can be achieved by exploiting specific interactions between drugs, and the ways in which resistance mutations to a given drug can modulate these interactions or increase the sensitivity of the bacteria to other compounds. Although their practical application requires much further development and validation, and relies on advances in genomic diagnostics, these discoveries suggest novel paradigms that may restrict or even reverse the evolution of resistance.

Antimicrobial combinations: Bliss independence and Loewe additivity derived from mechanistic multi-hit models

“…Except for a few clear-cut cases in which one of the inhibitors is effective only in combination with the other [10,32], or in the case of suppression [19,33], the classification of a combination as synergistic or antagonistic depends on the reference model. For high concentrations of inhibitors, Bliss independence is the more conservative choice of a reference model if one seeks to determine synergistic effect.…”

A New Natural Product Analog of Blasticidin S Reveals Cellular Uptake Facilitated by the NorA Multidrug Transporter

“…Considering the importance of multidrug resistance conferred by MFS transporters in clinical pathogenic bacteria, directional promiscuity could be exploited as a mechanism to select against resistance conferred by this protein family. The concept of cycling antibiotics in this way to apply opposing selection pressures during a course of treatment has been explored by a number of recent studies (55)(56)(57).…”

Interacciones evolutivas como un posible mecanismo de interacción medicamentosa: una aproximación para el control de la resistencia bacteriana

“…• Aquellas que tienen un mecanismo a nivel farmacocinético (las concentraciones plasmáticas del medicamento se ven afectadas por variaciones a nivel de la absorción, distribución, metabolismo y excreción del medicamento) y • Las IMs que se presentan a nivel farmacodinámico (se presenta modificación en la respuesta terapéutica, sin modificaciones en las concentraciones plasmáticas), también conocidas como interacciones fisiológicas 6 .…”

“…Relacionado con los antimicrobianos, la modificación en el efecto terapéutico de un antimicrobiano puede aparecer como consecuencia a la exposición previa a un antimicrobiano, concepto excluido de las definiciones de las IMs farmacocinéticas y farmacodinámicas 6 . Las interacciones evolutivas establecen que el desarrollo de susceptibilidad o resistencia de un microorganismo a un antimicrobiano tendrán un efecto inverso o similar en un segundo antimicrobiano que se incorpore a este sistema.…”