# Biofilm Lifestyle in Recurrent Urinary Tract Infections
## 6 Strategies for Eradication of Biofilms
### Targeting QS System  
QS system plays a pivotal role in controlling diverse bacterial virulence factors. In particular, it orchestrates the formation of microbial biofilms at different stages of infection [119; 120]. Additionally, QS regulates the production of different exoenzymes and other virulence factors in biofilms [40; 53; 121]. That is why targeting QS is a promising approach to diminishing biofilm formation, as well as minimizing bacterial virulence, which would pave the way for the immune system to eradicate the infection [41]. Targeting QS system guarantees attenuation of the bacterial virulence that could ease the immunity task in eradication of bacterial infections and their biofilms [122; 123]. Using anti-QS agents at sub-inhibitory concentrations is crucial for the success of the strategy, since higher concentrations would affect bacterial growth, which is considered a stress factor that directs bacteria towards developing resistance to the used antibiotics [58; 122; 124; 59]. As described in an earlier section, the QS system works in an inducer-receptor manner (Figure 3), and its blockade can be achieved by: (i) blocking of biosynthesis of inducers, (ii) inactivation of the inducers, and (iii) interference with involved QS receptors and involved proteins [50; 125; 126; 127]. In this direction, several chemical moieties and natural products were screened for their ability to block QS receptors and downregulate the expression of autoinducers [128; 129; 130; 131; 132; 133; 134; 135; 136; 137].  
The amino donor S-adenosyl methionine (SAM) is used in the production of homoserine lactone ring moiety (AHLs) in different Gram-negative bacteria [138; 139; 140]. SAM analogs (such as S-adenosylhomocysteine, S-adenosylcysteine, and other AHL analogs) can act as effective competitive inhibitors of the biosynthesis of AHL molecules, thereby diminishing bacterial virulence and biofilm formation [139; 141]. On a similar basis, macrolide antibiotics such as azithromycin and erythromycin showed a significant ability to inhibit the biosynthesis of AHLs in _P. aeruginosa_, with subsequent diminishing of biofilm formation when used at sub-minimum inhibitory concentrations [142; 143]. Likewise, it was reported in multiple studies that some chemical moieties showed a considerable ability to block QS receptors through downregulation of the autoinducer synthetase encoding genes. One example is observed in glipftims--a widely-used group of anti-diabetic agents--which were screened for their anti-QS activities. Notably, stiagliptin was shown to significantly downregulate the genes encoding autoinducer synthetase in _S. aureus_, _P. aeruginosa_ and _Serratia marcescens_, which resulted in blocking of QS receptors and subsequently diminished biofilm formation and virulence expression [62; 144; 145; 146]. Another approach that involved enzymatic degradation of QS inducers by AHL lactonases was also studied; such enzymes were able to degrade the homoserine lactone ring and stop QS signaling system, which in turn reflected a significant inhibition of bacterial virulence and biofilm inhibition [147; 148; 149].  
Another technique involves the downregulation of the genes encoding QS receptor/inducer system encoding genes, which would eventually diminish bacterial virulence as well as biofilm formation [51; 56; 150; 151]. It was shown that in _Pseudomonas aeruginosa_, downregulation of the Lux-type QS components LasI/R and Rhl/R, and non-Lux-type QS PqsA/R, confers significant inhibition of virulence as well as biofilm formation [62; 130; 137; 145; 152; 153]. _Salmonella_ and _E. coli_ rely on Lux-type homologous SdiA to sense diverse AHLs; interestingly, mutations in the _sdiA_ gene lead to significant reduction in the production of biofilms [136; 154; 46]. Similarly, ATP synthetase is an essential compartment in the Agr QS system in _Staphylococcus_ spp., and its targeting leads to significant inhibition of biofilm formation [62].