Bacteria are known to regulate their cooperative activities & physiological processes through a mechanism called “Quorum Sensing” (QS), in which bacteria communicate within themselves or within different species by releasing, sensing & responding to small diffusible signal molecules eg; Acylated homoserine lactones (AHLs) named as Autoinducer. QS allows microorganisms to control the behaviour of the entire bacterial population by secreting these signalling molecules. When the concentration of signal molecules reaches a certain threshold with bacterial population density, the expression of certain specific genes gets activated to regulate the bacteria population to undergo adaptation. These adaptations may activate a variety of cellular processes including virulence, drug resistance mechanism, tolerate antibiotics, biofilm formation in order to harm the host. QS exists in various bacteria, whether in Gram negative or Gram positive , but signal molecules they use to transmit information varies as different like human languages.
Antibiotics are used widely around the world besides antibiotic resistance is spreading faster than ever before. It takes 10-15 years to develop a new antibiotic but by this period bacteria become resistant to that drug, which is a serious problem to be considered. Most antibiotics currently used are designed to directly kill pathogenic bacteria. This “life or death” has caused them selection pressure promoting the evolution of microbial resistance and has become serious threats to human health. The large-scale use of antibiotics in the clinical treatment had led to multi-resistance mechanisms by microorganisms against the target of antibiotics.
Microbial Resistance mechanisms
1. Passivation of antibiotics through the chemical modification
Microorganism produces certain chemicals that inactivate the mechanism of the drug. By secretion of a modified enzyme changes the chemical structure of antibiotic drugs leading to inactivation or loss of activity of antibiotics. The enzymatic mechanism includes antibiotic degradation and derivatization of antibiotic chemical groups which leads to inactivating the drugs or destroying the molecules themselves so that no longer antibiotics can interact with microorganisms. eg; Bacterial enzyme, Beta-lactamase destroys the active component(the beta-lactam ring) of penicillins.
2. Efflux pump systemic
Here microorganisms use antibiotic pumps to expel antibiotics. Antibiotics usually enter the cell through the cell membrane in order to effectively attack specific targets. Microorganisms assemble efflux pump protein on their cell membrane to expel antibiotic drugs from cells. Bacterial efflux pumps are composed of the outer membrane channel protein, the fusion protein, and cytoplasmic efflux protein. Any foreign particle including protein, antibiotics is selectively or non-selectively eliminated from bacteria. Excretion rate is usually faster than drug penetration rate, thereby controlling drug level in the cell to non-sensitive level. They even have a variety of microbial efflux pump system such as lipophilic, hydrophilic efflux system that targets drugs of different chemical properties.
3. Modification of drug trageting genes
Microbes have evolved different strategies, which include modifying the target site, thereby reducing the affinity for antibiotic molecules to bind to the target site.
4. Biofilm Formation
Biofilm is an effective drug barrier, which significantly reduces antibiotic permeability. Bacteria are connected to each other through proteins & DNA, especially extracellular polysaccharides forming insurmountable barriers, which can reduce the permeability of antibiotic drugs & improve the survival rate of bacteria in the biofilm. Biofilms provide protection to microorganisms for altered PH, osmolarity, nutrients, mechanical or shear forces & also blocks access to antibiotics and the host’s immune cells.
This special environment in the biofilm makes bacteria in the membrane produce heterogeneity & produce antibiotics against other bacteria. Heterogeneity of bacteria has led to different levels of drug resistance against bacterial cells, where new research is emphasized more in this area.
It is essential for microbes to adapt & cope with these stressful situations. Thus a bacteria have devised complex mechanisms. Multiple drug resistance mechanisms expressed by these microorganisms had made it difficult to overcome and solve the problem of microbial resistance. In the struggle b/w microorganisms & antibiotics, more & more microorganisms have evolved multiple resistance mechanisms & have become “super bacteria”. Currently inhibiting bacterial QS has become a new promising antibacterial strategy.
Coumarin’s showed a Anti-Quorum Sensing Activity
Coumarins are a class of natural compounds based on benzopyrones. Coumarins are identified as secondary metabolites in about 150 different plant species. 7,8-dihydroxy-4-methylcoumarin was identified as the most effective anti-QS compound which had the ability to inhibit cell-to-cell communication in bacterial communities. At the same time when we look at its structural features, particularly the hydroxy group positions, well-responded to all anti-QS active coumarins. It was significantly noted as an increase in the antibacterial effect upon the hydroxylation of coumarins at positions 6,7, or 8. It showed that hydroxylation at position 7 increased anti-QS activity, while hydroxylation of coumarin at positions 6 & 7 decreased this activity in comparison to conventional coumarin. It also showed that Coumarin when combined with other Plant-Derived small molecules showed an effective response. 7.8-dihydroxy-4-methylcoumarin with 4-hexyl-1.3-benzendiol and gamma-octalactone demonstrated a synergetic anti-QS effect. Coumarins are characterized by a special mechanism through inhibition of the metabolism of cyclic 3,5-diguanylate (c-di-GMP), an intracellular intermediate involved in the regulation of bacterial exopolysaccharide synthesis, biofilm formation, adhesion, and virulence. Besides Coumarins are proposed for medical uses due to their proven biological activity such as Anti-inflammatory, Anti-ulcerogenic, Anticoagulant & are also Antioxidants.
Ref;https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7143945/ ; https://www.mdpi.com/2076-2607/8/3/425/htm
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