Ever-Adapting RND Efflux Pumps in Gram-Negative Multidrug-Resistant Pathogens: A Race against Time

Abstract

The rise in multidrug resistance (MDR) is one of the greatest threats to human health worldwide. MDR in bacterial pathogens is a major challenge in healthcare, as bacterial infections are becoming untreatable by commercially available antibiotics. One of the main causes of MDR is the over-expression of intrinsic and acquired multidrug efflux pumps, belonging to the resistance-nodulation-division (RND) superfamily, which can efflux a wide range of structurally different antibiotics. Besides over-expression, however, recent amino acid substitutions within the pumps themselves—causing an increased drug efflux efficiency—are causing additional worry. In this review, we take a closer look at clinically, environmentally and laboratory-evolved Gram-negative bacterial strains and their decreased drug sensitivity as a result of mutations directly in the RND-type pumps themselves (from Escherichia coli, Salmonella enterica, Neisseria gonorrhoeae, Pseudomonas aeruginosa, Acinetobacter baumannii and Legionella pneumophila). We also focus on the evolution of the efflux pumps by comparing hundreds of efflux pumps to determine where conservation is concentrated and where differences in amino acids can shed light on the broad and even broadening drug recognition. Knowledge of conservation, as well as of novel gain-of-function efflux pump mutations, is essential for the development of novel antibiotics and efflux pump inhibitors.

Candidates for Repurposing as Anti-Virulence Agents Based on the Structural Profile Analysis of Microbial Collagenase Inhibitors

“…The ioxitalamic acid, technetium tc-99 m disofenin, mebrofenin, and betiatide are all used for diagnostic purposes and have a low druglike character because of their toxicity risks [61,62]. Chloramphenicol succinate and nafcillin are antimicrobial drugs [63] and their effects on bacterial growth can promote resistant strains limiting their development as BCI. Benzthiazide (thiazide diuretic), entacapone (catechol-O-methyltransferase inhibitor, Parkinson's disease) and lodoxamide (mast cell stabilizer, antiallergic) emerged as the best candidates for development as antivirulence agents in infections with pathogens form the Clostridium, Pseudomonas, Vibrio, and Streptomyces genuses.…”

Complete Genome Sequence of SMBL-WEM22, a Halotolerant Strain of Kosakonia cowanii Isolated from Hong Kong Seawater

“…CARD/RGI v5.2.0 identified putative antimicrobial resistance (AMR) genes, including multidrug efflux systems AcrAB-TolC and MdtABC-TolC ( 17 , 18 ). The OmpR/EnvZ osmoregulation pathway was found using KASS ( 12 , 13 , 19 , 20 ).…”

A role for the periplasmic adaptor protein AcrA in vetting substrate access to the RND efflux transporter AcrB

“…Antibiotic resistance is one of the greatest global public health challenges and threatens our ability to effectively treat and prevent infectious diseases 1 . In clinical isolates of Gram-negative bacteria, the Resistance-Nodulation-Division (RND) family of efflux pumps are frequently upregulated and associated with multidrug-resistant phenotypes 2 – 6 . Tripartite RND pumps span the double membrane of Gram-negative bacteria and consist of an inner membrane RND transporter, a periplasmic adaptor protein (PAP), and an outer membrane factor (OMF) 7 , 8 .…”