Creative targeting of the Gram-negative outer membrane in antibiotic discovery

Overview

The bacterial cell wall is an essential structural component that encases the plasma membrane, preserving cellular integrity, determining shape, and protecting against osmotic stress. This rigid yet flexible structure primarily comprises peptidoglycan, a polymer that forms a mesh-like matrix conferring mechanical strength and flexibility.Peptidoglycan Composition and StructurePeptidoglycan, the core of the bacterial cell wall, comprises alternating units of N-acetylglucosamine (NAG) and...

Antibiotic resistance is a major public health concern that arises when bacteria evolve mechanisms to withstand the effects of antibiotic treatments. This resistance can be intrinsic, acquired through genetic mutations, or transferred between bacteria via horizontal gene transfer. The development of antibiotic resistance poses significant challenges in treating bacterial infections and necessitates ongoing research to develop new therapeutic strategies.Intrinsic resistance occurs when bacterial...

Gram-negative bacteria utilize sophisticated protein secretion systems to transport proteins across their double-membrane envelope into the extracellular environment or host cells. Based on their mechanism of action, these systems are classified into one-step and two-step pathways.One-Step Secretion Systems (Types I, III, IV, and VI)One-step secretion systems bypass the periplasm entirely, forming a continuous channel that spans both the inner and outer membranes:Type I Secretion System (T1SS):...

Synergism is a useful mechanism where combining two or more drugs is more effective than each constituent used alone. Such combinations are also called supra-additive interactions. The drugs collectively enhance the final therapeutic effect by acting on different targets. Another advantage is that the low dose of each constituent drug is sufficient to achieve the desired effect. This helps reduce the duration of therapy and lower the adverse effects of these drugs.
Such synergistic combinations...

Quorum sensing is a mechanism of bacterial communication that enables coordinated gene expression in response to changes in population density. This facilitates collective behaviors that enhance survival, resource acquisition, and ecological adaptation. This process relies on small signaling molecules called autoinducers that accumulate as bacterial populations grow. When a critical threshold concentration of autoinducers is reached, bacterial cells collectively modify gene expression,...