Even the layman has now become aware about the fact that one of the greatest challenge that the medical and scientific community is currently facing is the growing antibiotic and antimicrobial resistance against the already employed antibiotics, famously known as the “The Antibiotic Resistance Crisis”.
The escalating menace of antibiotic resistance represents a profound peril to global public health.
This problem just seems to be increasing as time passes by and it’s further augmentation imperils our capacity to combat commonplace infections, transforming previously manageable maladies into potential life-threatening afflictions.
The list of the most dangerous pathogens in need of antimicrobial drug development according to the WHO
This is just to name a few that has already terrorized us. Here, we are going to discuss a way that our scientists have found out to combat this grave problem.
But before we do that, let us understand broadly why antibiotic resistance happens at a molecular level and how that can be counteracted by practical reasoning, following are the examples:
The four main mechanisms of antibiotic resistance in Gram-negative organisms (blue boxes) are
(i) antibiotic inactivation, for example, the production of β-lactamase enzymes that hydrolyse the β-lactam ring thereby deactivating this class of antibiotics; which is the case for beta-lactamase-producing Enterobacteriaceae (ESBLs)
(ii) target modification, for example modifications in the GyrA protein confers resistance to fluoroquinolones; for eg: Pseudomonas aeruginosa and Acinetobacter baumannii
(iii) active efflux, where drug efflux pumps remove the antibiotic from the bacterial cell thereby lowering antibiotic concentration to sub-toxic levels, that is happens in methicillin-resistant Staphylococcus aureus (MRSA)
(iv) prevention of drug entry through the OM by the expression of more selective porins, mutations in porins or loss of porins, which is seen in E. Coli.
In 2022, a paper published by Dr Christopher Furniss, titled “Breaking antimicrobial resistance by disrupting extracytoplasmic protein folding” gave us a new groundbreaking research to reverse antibiotic resistance and again make the bacteria vulnerable to antibiotics. The approach represented a completely new way of thinking about targeting resistance.
"Since the discovery of new antibiotics is challenging, it is crucial to develop ways to prolong the lifespan of existing antimicrobials." Dr Chris Furniss
This paper is one of the first reports of a strategy capable of simultaneously impairing multiple types of AMR(Anti- microbial resistance) determinants by compromising the function of a single target. By inhibiting DsbA, a non-essential cell envelope protein which is unique to bacteria, we can inactivate diverse resistance enzymes and sensitize critically important pathogens to several existing antibiotics.
In extracytoplasmic environments protein stability often relies on the formation of disulfide bonds between cysteine residues. Notably, in the cell envelope of Gram-negative bacteria this process is performed by a single pathway, the DSB system, and more specifically by a single protein, the thiol oxidase DsbA . DsbA has been shown to assist the folding of hundreds of proteins in the periplasm including a vast range of virulence factors. As such, inhibition of DSB proteins has been shown as a promising broad-acting strategy to target bacterial pathogenesis without impairing bacterial viability. Since several cell envelope AMR determinants contain multiple cysteines , they proved that interfering with the function of DsbA would not only compromise bacterial virulence, but also offers a broad approach to break resistance across different mechanisms by affecting the stability of resistance proteins.
They demonstrated that disruption of cell envelope protein homeostasis simultaneously compromises several classes of resistance determinants. In particular, we find that impairing DsbA-mediated disulfide bond formation incapacitates diverse β-lactamases and destabilizes mobile colistin resistance enzymes. Furthermore, they show that chemical inhibition of DsbA sensitizes multidrug-resistant clinical isolates to existing antibiotics and that the absence of DsbA, in combination with antibiotic treatment, substantially increases the survival of Galleria mellonella larvae infected with multidrug-resistant Pseudomonas aeruginosa.
Conclusion
The “Antibiotic resistance crisis” keeps on increasing in magnitude. The study of 2022 has opened several avenues for the development of novel antibiotic adjuvants with the potential to revolutionize therapeutic and treatments strategies.
References:
4. https://www.imperial.ac.uk/news/234060/scientists-discover-approach-fighting-antibiotic-resistance/
by- JOOHI GADODIA
Well researched and well written .
Very good research