195
quorum quenching properties inhibits biofilm formation, virulence factor production and antimicrobial resistance in pathogenic bacteria (Rasmussen et al. 2005;
Harjai et al. 2010). A pyrimidine analog, 5-Fluorouracil (5-FU) inhibits the quorum
sensing regulated expression of genes involved in the virulence of resistant P. aeruginosa. Nowadays, 5-FU is being used in the coating of catheters (Ueda et al. 2009).
In clinical trials, the results of coated catheters were shown to be significant in terms
of biofilm disruption formed by antibiotic resistant bacteria (Walz et al. 2010).
ET37 molecule, N-(3-oxododecanoyl) homoserine lactone (3O-C12-HSL) conjugated with ciprofloxacin was found to be significant to reduce the biofilm formation
and enhance the antibiotic susceptibility in P. aeruginosa (Bortolotti et al. 2019). In
vitro studies on Sinefungin also showed reduced pneumococcal biofilm growth.
Sinefungin has been shown to inhibit the synthesis of AI-2 via downregulating the
expression of luxS, pfs, and speE (Yadav et al. 2014). In a recent study, results
showed that curcumin in combination with tobramycin, gentamicin, and azithromycin shows synergistic effects against P. aeruginosa. This combination reduces the
quorum sensing associated virulence factors by downregulation of the quorum sensing genes (Bahari et al. 2017). Another anti quorum sensing agent Farnesol administered in combination with β-lactam antibiotics attenuated the growth rate of
methicillin resistant Staphylococcus aureus. This combination inhibits the lipase
activity and disrupt cytoplasmic membrane through the leakage of potassium ions
(Kim et al. 2018).
8.8 Challenges and Prospects in the Development of Quorum
Quenching Inhibitors as Therapeutic Agents
The previous studies on the role of quorum sensing in the bacterial pathogenicity
and resistance to antibiotics led the concept of quorum quenching or quorum sensing inhibitors to be used in pharmaceuticals for disease control. The quorum sensing
mutants of pathogenic bacteria were found to be attenuated for virulence. A wide
number of inhibitor molecules and quenching enzymes have been discovered as an
alternative to antibiotics due to the emergence of resistance. Yet, we are still facing
the obstacle in their clinical use. The major hurdles to use them in the clinic are their
toxicity, delivery, stability, potency and narrow activity spectrum. In addition to
that, some questions are still unanswered and open ended. At what stage of infection
will quorum sensing inhibition be of value? Which pathogen should be targeted? Is
there any resistance to quorum sensing inhibitors? What are the mechanisms of
quorum quenching? Are only quorum sensing inhibitors are sufficient to control the
disease/ infections caused by resistant bacteria or should be used in combination
with other antimicrobials for synergistic effects? Future investigations are required
to determine the breadth of the mechanism of action of quorum quenching inhibitor
molecules and their potential in being used as an alternative for the mitigation of
antibiotic resistance.
8 Intrusion of Bacterial Quorum-Sensing for Antimicrobial Resistance Mitigation…
quorum quenching properties inhibits biofilm formation, virulence factor production and antimicrobial resistance in pathogenic bacteria (Rasmussen et al. 2005;
Harjai et al. 2010). A pyrimidine analog, 5-Fluorouracil (5-FU) inhibits the quorum
sensing regulated expression of genes involved in the virulence of resistant P. aeruginosa. Nowadays, 5-FU is being used in the coating of catheters (Ueda et al. 2009).
In clinical trials, the results of coated catheters were shown to be significant in terms
of biofilm disruption formed by antibiotic resistant bacteria (Walz et al. 2010).
ET37 molecule, N-(3-oxododecanoyl) homoserine lactone (3O-C12-HSL) conjugated with ciprofloxacin was found to be significant to reduce the biofilm formation
and enhance the antibiotic susceptibility in P. aeruginosa (Bortolotti et al. 2019). In
vitro studies on Sinefungin also showed reduced pneumococcal biofilm growth.
Sinefungin has been shown to inhibit the synthesis of AI-2 via downregulating the
expression of luxS, pfs, and speE (Yadav et al. 2014). In a recent study, results
showed that curcumin in combination with tobramycin, gentamicin, and azithromycin shows synergistic effects against P. aeruginosa. This combination reduces the
quorum sensing associated virulence factors by downregulation of the quorum sensing genes (Bahari et al. 2017). Another anti quorum sensing agent Farnesol administered in combination with β-lactam antibiotics attenuated the growth rate of
methicillin resistant Staphylococcus aureus. This combination inhibits the lipase
activity and disrupt cytoplasmic membrane through the leakage of potassium ions
(Kim et al. 2018).
8.8 Challenges and Prospects in the Development of Quorum
Quenching Inhibitors as Therapeutic Agents
The previous studies on the role of quorum sensing in the bacterial pathogenicity
and resistance to antibiotics led the concept of quorum quenching or quorum sensing inhibitors to be used in pharmaceuticals for disease control. The quorum sensing
mutants of pathogenic bacteria were found to be attenuated for virulence. A wide
number of inhibitor molecules and quenching enzymes have been discovered as an
alternative to antibiotics due to the emergence of resistance. Yet, we are still facing
the obstacle in their clinical use. The major hurdles to use them in the clinic are their
toxicity, delivery, stability, potency and narrow activity spectrum. In addition to
that, some questions are still unanswered and open ended. At what stage of infection
will quorum sensing inhibition be of value? Which pathogen should be targeted? Is
there any resistance to quorum sensing inhibitors? What are the mechanisms of
quorum quenching? Are only quorum sensing inhibitors are sufficient to control the
disease/ infections caused by resistant bacteria or should be used in combination
with other antimicrobials for synergistic effects? Future investigations are required
to determine the breadth of the mechanism of action of quorum quenching inhibitor
molecules and their potential in being used as an alternative for the mitigation of
antibiotic resistance.
8 Intrusion of Bacterial Quorum-Sensing for Antimicrobial Resistance Mitigation…