Overcoming Intrinsic and Acquired Resistance Mechanisms Associated with the Cell Wall of Gram-Negative Bacteria

Abstract

The global increase in multi-drug-resistant bacteria is severely impacting our ability to effectively treat common infections. For Gram-negative bacteria, their intrinsic and acquired resistance mechanisms are heightened by their unique cell wall structure. The cell wall, while being a target of some antibiotics, represents a barrier due to the inability of most antibacterial compounds to traverse and reach their intended target. This means that its composition and resulting mechanisms of resistance must be considered when developing new therapies. Here, we discuss potential antibiotic targets within the most well-characterised resistance mechanisms associated with the cell wall in Gram-negative bacteria, including the outer membrane structure, porins and efflux pumps. We also provide a timely update on the current progress of inhibitor development in these areas. Such compounds could represent new avenues for drug discovery as well as adjuvant therapy to help us overcome antibiotic resistance.

Antimicrobial Resistance in Escherichia coli Strains Isolated from Humans and Pet Animals

“…E. coli and other gram-negative bacteria have two important characteristics, which are the foundations of their intrinsic resistance. Namely, they have a protective impermeable membrane and a large number of efflux pumps, which successfully remove all unwanted substances from inside the cell [ 107 , 108 , 109 ].…”

Adaptive Drug Resistance in Malaria Parasite: A Threat to Malaria Elimination Agenda?

“…Drug resistance types include Intrinsic, acquired and adaptive resistance. Intrinsic drug resistance is a natural phenomenon, and an innate ability in pathogen for resisting drug or harmful substance without prior record of susceptibility [30,31], pathogens do not necessarily develop mutation for this to occur [32]. Acquired drug resistance builds up in human host, and makes them unresponsive to a drug that should normally eliminate known pathogenic parasite from the host system [33], these are both stable forms of drug resistance.…”

In Vivo Evaluation of a Recombinant N-acylhomoserine Lactonase Formulated in a Hydrogel Using a Murine Model Infected With Mdr Pseudomonas Aeruginosa Clinical Isolate, CCASUP2

“…The low permeability of its membrane and the constitutive expression of various e ux pumps render P. aeruginosa intrinsically resistant to several antibiotics. In addition to this, P. aeruginosa produces antibiotic-inactivating enzymes which can develop or acquire new mechanisms of resistance to antibiotics (Mesaros et al 2007;Impey et al 2020). All this caused P. aeruginosa to be among the so-termed "Superbugs" (Breidenstein et al 2011).…”