In a recent review published in npj Antimicrobials and Resistance, researchers reviewed existing data on next-generation antimicrobial agents (NGAs) as a potential alternative to standard antibiotics or an effective technique for extending antibiotic efficacy when combined.
The influence of antimicrobials on health is eroding rapidly due to the advent of bacteria resistant to multiple drugs.
There is widespread agreement that new infection-fighting tactics are required urgently to reduce the devastating effects of antimicrobial resistance (AMR) on global healthcare systems.
Study: Using next generation antimicrobials to target the mechanisms of infection. Image Credit: fizkes/Shutterstock.com
About the review
In the present review, researchers addressed the need for, development issues with, and mechanisms of action of NGAs that might provide a viable alternative to standard antibiotic usage or potentially prolong the efficacy of frontline antibiotics when combined with other agents.
The need for NGAs and challenges in the development
Antimicrobials work by delaying or killing bacteria by targeting important functions of bacteria, such as translation, transcription, cell wall formation, and deoxyribonucleic acid (DNA) replication. AMR evolves as a result of this negative-type selection pressure on microorganisms.
The rise of multidrug-resistant (MDR) microbes, as well as the distribution of resistance-inducing genetic components, has resulted in a decrease in the efficacy of frontline antibiotics, posing considerable danger to the global healthcare system.
Climatic changes have exacerbated the AMR epidemic, with greater regional ambient temperatures linked to increased AMR prevalence.
Over the previous three decades, the decrease in newly manufactured and licensed antibiotics has resulted in the collapse of clinical development procedures and infrastructure.
The time and costs required to bring novel antibiotics to market have demotivated pharmaceutical industries, causing large pharmaceutical firms to halt their antimicrobial development pipelines and start-ups to fail.
This migration has left the healthcare system vulnerable, increasing mortality from antimicrobial-resistant infections.
Mechanisms of action for NGA development
NGAs attack bacterial virulence factors to destroy pathogenic potential while preserving bacterial survival. These chemicals make infections more sensitive to immune clearance and, as a result, perhaps more amenable to standard antibiotics.
At doses that reduce selection pressure and resistance development, NGAs exhibit antivirulence characteristics.
Developing NGAs that undermine the structural configuration of bacterial biofilms could be a potential method. Extracellular enzymes such as the sporulation-specific extracellular nuclease (NucB), pyocyanin demethylase (PodA), and deoxyribonuclease I (DNase I) cause forced cellular dispersal from biofilms into the environment in an antimicrobial-sensitive planktonic form.
In biofilms, extracellular deoxyribonucleic acid (eDNA) serves as a structural template within the extracellular matrix and could control aggregation and adherence to host tissues. DNA-binding proteins are essential for the biofilm matrix's adherence, structuring, and stability.
It has been demonstrated that directing the immunological system toward biofilm-associated proteins severely disrupts the structural integrity of extracellular DNA and the biofilm.
Antisera against DNABII proteins like the integration host factor A (IhfA) can disrupt biofilms generated by the ESKAPE pathogenic organisms (Enterococcus faecium, Staphylococcus aureus species, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species).
Antisera-based methods have also been demonstrated to enhance deoxyribonuclease-induced biofilm destruction and antibiotic killing, as well as boost macrophages' ability to fight bacteria.
Another approach for developing NGAs is to target extracellular polysaccharides. Extracellular polysaccharides secreted by cells are important matrix constituents, contributing to biofilm formation and persistence.
However, considering the type and location of the infection, their potential ability to send planktonic cells and aggregates into the microenvironment, facilitating bacterial dissemination to different sites of infection or triggering bacteremia, should be considered.
Global virulence regulation pathways can be targeted to construct NGAs and battle many virulence factors simultaneously without directly affecting bacterial growth. Disrupting these pathways is a viable method for the development of NGAs.
Toxin functionality in bacteria may be targeted to restrict illness, and secretion systems can be targeted with NGAs at the component expression, apparatus assembly, toxin localization, or toxin activity levels.
Plant extracts are a rich source of phytochemicals with therapeutic potential and the ability to target particular pathways in bacteria. Due to evolutionary forces, some plant extracts have better absorption, distribution, metabolism, excretion, and toxicity (ADMET) characteristics.
However, finding active chemicals and comprehending biological targets is difficult. Nonetheless, phytochemicals have the potential to repurpose authorized medications as NGAs, with off-target anti-virulence effects on bacteria and dietary components as examples.
Based on the review findings, the need for novel therapeutic strategies to combat MDR infections is urgent, with NGAs a promising approach. Targeting biofilms, extracellular DNA, and toxin functionality can reduce toxicity; however, robust screening is required for off-target effects.
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