Role of mycobacterial efflux transporters in drug resistance: an unresolved question

Abstract

Two mechanisms are thought to be involved in the natural drug resistance of mycobacteria: the mycobacterial cell wall permeability barrier and active multidrug efflux pumps. Genes encoding drug efflux transporters have been isolated from several mycobacterial species. These proteins transport tetracycline, fluoroquinolones, aminoglycosides and other compounds. Recent reports have suggested that efflux pumps may also be involved in transporting isoniazid, one of the main drugs used to treat tuberculosis. This review highlights recent advances in our understanding of efflux-mediated drug resistance in mycobacteria, including the distribution of efflux systems in these organisms, their substrate profiles and their contribution to drug resistance. The balance between the drug transport into the cell and drug efflux is not yet clearly understood, and further studies are required in mycobacteria.

Determinación de la mutación S315T del gen katG en aislados resistentes a Isoniacida de Mycobacterium tuberculosis mediante PCR-RFLP

“…Estos resultados difieren de trabajos previos publicados en los cuales solo se reporta la presencia de perfiles de mutación en la posición S315T en aislados resistentes 7,19,20,22,31 , el 25,5% de aislados fenotipicamente resistentes que no presentaron la mutación estudiada, pudo deberse a la presencia de polimorfismos en regiones diferente a la posición S315T [15][16][17][18][19][20] en el gen katG u otros genes que aporten resistencia a Isoniacida 9-14 indiciendo a la sobreexpresión que superen el poder inhibitorio de INH 26,31 ; otra causa puede ser la presencia de mecanismos de resistencia diferente a las mutaciones tales como mecanismos de barrera (reducción de la permeabilidad 32-33 y bomba de eflujo [34][35][36][37] ). En cuanto a la presencia de un aislado sensible con la mutación S315T, posiblemente se deba a que el límite de la detección por PCR-RFLP empleada se encuentre cercano al 1% de resistentes que basado en el método de las proporciones pasa imperceptible y se considera como sensible, tambien podría deberse a una inadecuada identificación del perfil de resistencia mediante la prueba de las proporciones en el aislado sensible, y/o contaminación del aislado después de su conservación.…”

Characterization of the MSMEG_2631 Gene ( mmp ) Encoding a Multidrug and Toxic Compound Extrusion (MATE) Family Protein in Mycobacterium smegmatis and Exploration of Its Polyspecific Nature Using Biolog Phenotype MicroArray

“…For Mycobacterium intrinsic drug resistance, strong support exists for a major role for low cell wall permeability (15,16) and an array of efficient multidrug efflux pumps (17). LfrA, an MFS efflux pump that confers resistance to fluoroquinolones, EtBr, acridine, and quaternary ammonium compounds, was the first such pump characterized in mycobacteria (53).…”

“…LfrA, an MFS efflux pump that confers resistance to fluoroquinolones, EtBr, acridine, and quaternary ammonium compounds, was the first such pump characterized in mycobacteria (53). More recently, other efflux pumps have been demonstrated to be involved in mycobacterial drug resistance (17). Several approaches were used in these studies: (i) monitoring drug resistance change due to efflux gene expression in a suitable host, which suggests involvement in efflux but which does not demonstrate an endogenous role or physiological importance; (ii) genome-wide expression analysis in response to drugs, which can identify inducible efflux genes and provide insights into their importance during drug exposure but which cannot identify constitutively expressed genes; (iii) monitoring drug resistance changes due to efflux gene deletion, which is a straightforward strategy but works only if the genes of interest encode a dominant efflux protein and other genes do not encode proteins with similar specificity (which may mask the effect of deletion).…”

“…These strategies may be an intrinsic feature of an organism or acquired via mutations or acquisition of exogenous genes (13,14). Low mycobacterial cell wall permeability due to its lipid-rich composition, limiting drug entry, is one reason for intrinsic resistance (15,16), but Mycobacterium also has several multidrug efflux pumps (17) that enhance drug resistance by drug extrusion; however, their roles in intrinsic resistance are not well explored.…”

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“…CCCP and DNP disperse the membrane PMF with the advancement of the trans-membrane electrochemical potential; thus, these compounds may be toxic to the cells. Also of this protonophores are also known as ionophores, and they work as chemical inhibitors of oxidative phosphorylation, serves to inhibit the activity of ATP synthase; therefore, CCCP and DNP have an effect on ABC superfamily pumps 14 .…”