RND efflux pump mediated antibiotic resistance in Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa: a major issue worldwide

Abstract

Therapeutic failures against diseases due to resistant Gram-negative bacteria have become a major threat nowadays as confirmed by surveillance reports across the world. One of the methods of development of multidrug resistance in Escherichia coli and Pseudomonas aeruginosa is by means of RND efflux pumps. Inhibition of these pumps might help to combat the antibiotic resistance problem, for which the structure and regulation of the pumps have to be known. Moreover, judicious antibiotic use is needed to control the situation. This paper focuses on the issue of antibiotic resistance as well as the structure, regulation and inhibition of the efflux pumps present in Escherichia coli and Pseudomonas aeruginosa.

Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

“…Many promising compounds have been patented, for example, pyranopyridines, peptidomimetics, and indole derivatives . However, no EPI has been clinically approved to date, mainly because of low in vivo efficacy, poor pharmacokinetic properties and/or toxicity problems . There have been some attempts to separate toxicity issues from EPI activity at stages of lead optimization.…”

“…185,249,263 However, no EPI has been clinically approved to date, mainly because of low in vivo efficacy, poor pharmacokinetic properties and/or toxicity problems. 20,61,62 There have been some attempts to separate toxicity issues from EPI activity at stages of lead optimization. For example, peptidomimetic analogs, in which the basic ornithine group was recognized as the major contributor to the observed in vivo toxicity but was also crucial for potentiation activity.…”

“…These are peptidomimetic PAβN ( 1 ), pyridopyrimidinone D13‐9001 ( 2 ), pyranopyridine MBX2319 ( 3 ), representatives of the quinoline ( 4 ), and of the indole ( 5 ) derivatives (Figure ). However, only a few EPIs have reached clinical trials, where they have failed due mostly to toxic effects at the concentrations essential for their activity, poor pharmacokinetic properties or low in vivo efficacy . To the best of our knowledge, only for one EPI that has made its way into clinical development, the structure is revealed.…”

“…However, only a few EPIs have reached clinical trials, where they have failed due mostly to toxic effects at the concentrations essential for their activity, poor pharmacokinetic properties or low in vivo efficacy. 20,[60][61][62] To the best of our knowledge, only for one EPI that has made its way into clinical development, the structure is revealed. This is a bis(pyrimidine)sulfonamide MP-601,205 (6; Figure 1) that was tested in the form of aerosol formulation in combination with the approved antibiotic ciprofloxacin for the treatment of respiratory infections in patients with cystic fibrosis and ventilator-associated pneumonia, caused by MDR Gram-negative bacteria, such as P. aeruginosa.…”

A palette of fluorophores that are differentially accumulated by wild-type and mutant strains ofEscherichia coli: surrogate ligands for bacterial membrane transporters

“…coli contains a great many 'efflux' pumps, mutations in which can cause substantial resistance to multiple drugs and antibiotics (e.g. [59][60][61][62][63][64][65]). Many are driven by ATP hydrolysis [66] though others obtain free energy via electron-transport-linked membrane energisation.…”