Functional Diversity of Gram-Negative Permeability Barriers Reflected in Antibacterial Activities and Intracellular Accumulation of Antibiotics.

Gram-negative bacteria are notoriously more resistant to antibiotics than Gram-positive bacteria, primarily due to the presence of the outer membrane and a plethora of active efflux pumps. However, the potency of antibiotics also varies dramatically between different Gram-negative pathogens, suggesting major mechanistic differences in how antibiotics penetrate permeability barriers. Two approaches are used broadly to analyze how permeability barriers affect intracellular accumulation of antibiotics.

Structure-Uptake Relationship Studies of Oxazolidinones in Gram-Negative ESKAPE Pathogens.

The clinical success of linezolid for treating Gram-positive infections paired with the high conservation of bacterial ribosomes predicts that if oxazolidinones were engineered to accumulate in Gram-negative bacteria, then this pharmacological class would find broad utility in eradicating infections. Here, we report an investigative study of a strategically designed library of oxazolidinones to determine the effects of molecular structure on accumulation and biological activity. , , and strains with varying degrees of compromise (in efflux and outer membrane) were used to identify motifs that hinder permeation across the outer membrane and/or enhance efflux susceptibility broadly and specifically between species.

Bacterial efflux transporters' polyspecificity - a gift and a curse?

All mechanisms of clinical antibiotic resistance benefit from activities of polyspecific efflux pumps acting to reduce intracellular accumulation of toxins and antibiotics. In Gram-negative bacteria, the major polyspecific efflux transporters belong to the Resistance-Nodulation-cell Division (RND) superfamily of proteins, which are capable of expelling thousands of structurally diverse compounds. Recent structural and functional advances generated novel insights into mechanisms underlying the biochemical versatility of RND transporters.

Role of Natural Product in Modulation of Drug Transporters and New Delhi Metallo-β Lactamases.

A rapid growth in drug resistance has brought options for treating antimicrobial resistance to a halt. Bacteria have evolved to accumulate a multitude of genes that encode resistance for a single drug within a single cell. Alternations of drug transporters are one of the causes for the development of resistance in drug interactions.

Use of succinic & oxalic acid in reducing the dosage of colistin against New Delhi metallo-β-lactamase-1 bacteria.

Background & Objectives: New Delhi metallo-β-lactamase 1 (NDM-1) cleaves the beta-lactam ring, and confers bacterial resistance against most of the beta-lactam antibiotics, except tigecycline and colistin. Among these two antibiotics, colistin is considered toxic, and therefore, its clinical use and dosage need cautious approach. In the present study, six organic acids were screened individually and in combination of two acids for their effectiveness against NDM-1 Escherichia coli and a combination of colistin and oxalic or succinic acid was tested to find out the potential of combination therapy for reducing the dose of toxic colistin.

Inhibition of New Delhi Metallo-β-Lactamase 1 (NDM-1) Producing IR-6 by Selected Plant Extracts and Their Synergistic Actions with Antibiotics.

Improper use of antibiotics has led to a great concern in the development of pathogenic microbial resistance. New Delhi metallo-β-lactamase 1 (NDM-1) producing bacteria are resistant to most of the β-lactam antibiotics, and so far, no new compounds have been clinically tested against these bacteria. In this study, ethanol extracts from the leaves of 240 medicinal plant species were screened for antibacterial activity against an NDM-1 strain.