# Development of Antibiofilm Therapeutics Strategies to Overcome Antimicrobial Drug Resistance
## 5 Emerging Antibiofilm Agents
### Quorum Quenching Agents  
The persister cells have the ability to communicate amongst themselves leading to virulence and the generation of resistance. Different quorum quenching agents have been  
\begin{table}
\begin{tabular}{c c c} \hline \hline
**Compound** & **R** & **Biofilm Inhibition Ratio (\%)** \\ \hline
2-hydroxy-4-methoxy-3-(3-methylbut-2-en-1-yl)-6-[(Z)-2- (pyrimidin-5-yl)]ethenyl[benzoic acid (**8a**) & 36.11 \(\pm\) 0.58 \\ \hline
2-hydroxy-4-methoxy-3-(3-methylbut-2-en-1-yl)-6-[(Z)-2- (quinolen-8-yl)]ethenyl[benzoic acid (**8b**) & 35.61 \(\pm\) 3.76 \\ \hline
2-hydroxy-4-methoxy-3-(3-methylbut-2-en-1-yl)-6-[(Z)-2- (sulfurenafluoro-benzene-4-yl)]benzoic acid (**8c**) & 49.50 \(\pm\) 1.35 \\ \hline \hline \end{tabular}
\end{table}
Table 4: Biofilm inhibition ratios for cajainnstilbene acid derivatives.  
\begin{table}
\begin{tabular}{c c c c c} \hline \hline \multirow{2}{*}{**Compound**} & \multirow{2}{*}{**R**} & \multicolumn{3}{c}{**Bacterial Biofilm Inhibition (IC50 in uM \(\pm\) SD)**} \\ \cline{3-5}  & & _S. aureus_ & _M. luteus_ & _P. aeruginosa_ \\ \hline (E)-N-(4-(3-(4-Chlorophenyl)acryloyl)phenyl)-3- (piperidin-1-yl)propanamide (**7a**) & 4-Cl & 2.4 \(\pm\) 0.10 & 4.8 \(\pm\) 0.11 & 7.8 \(\pm\) 0.24 \\ \hline (E)-N-(4-(3-(4-Methyloxyphenyl)acryloyl)phenyl)- (3-piperidin-1-yl)propanamide (**7b**) & 4-OCH\({}_{3}\) & 4.9 \(\pm\) 0.21 & 5.7 \(\pm\) 0.26 & 8.6 \(\pm\) 0.22 \\ \hline (E)-3-(piperidin-1-yl)-N-(4-(3-(3,4,5-trimethoxyyphenyl)acryloyl)phenyl)propanamide (**7c**) & 3,4-di(OCH\({}_{3}\)) & 2.9 \(\pm\) 0.16 & 5.6 \(\pm\) 0.22 & 0.84 \(\pm\) 0.21 \\ \hline \hline \end{tabular}
\end{table}
Table 3: IC50 values for amide chalcones.  
Figure 7: Chemical structure of cajainnstilbene acid derivatives.  
explored in order to find adjuvant therapy. The bacterial QS inhibitory effect of subtilisin (9), a cyclic lantibiotic formed by _B. subtilis_ KATMIRA1933, was assessed by [PERSON] et al. [162]. Subtilosin shows its effect by targeting the surface receptor and binding to the bacterial cell membrane by electrostatic forces. The study revealed that at a concentration of 15.1 \(\mu\)g/mL an inhibition of 80% of _L. monocytogenes_ and about 60% of _E. coli_ biofilms was seen. Moreover, subtilisin decreased the autoinducer-2 formation in _Gardnerella vaginalis_ at a concentration of 3-4 \(\mu\)g/mL [152]. [PERSON] et al. evaluated the QS inhibitory potential of hardening (**10**) isolated from sprouting barley towards _P. aeruginosa_. It was found to inhibit the autoinducer AHLs at concentrations of 0.5 to 1.0 mg/mL. Additionally, it also remarkably suppressed the QS associated genes _lasR_, _rhlR_, _rhlI_ and _lasI_[163]. In another work by [PERSON] et al. the QS inhibitory effect of falcarindoli (**11**) against _P. aeruginosa_ infestation was assessed. Biofilm formation and associated virulence factors were significantly inhibited at subinhibitory concentrations. Also, there was appreciable downregulation of the mRNA expression of QS associated genes _lasI_, _lasB_, _rhlA_, _pqsA_, _rhlR_, _phzH_ and _rhl I_[164]. QS and biofilm inhibitory effects of a few hardening derivatives towards _P. aeruginosa_ and _Serratia marcescens_ was recently analysed by [PERSON] et al. Derivatives **12a-g** exhibited superior QS inhibitory activity and biofilm inhibition towards _P. aeruginosa. Additionally, analogues **12a-c** and **12g** displayed remarkable QS inhibition against _S._ marcescens. SAR studies revealed essential factors involved in activity like alkyl chain length, presence or absence of amino or hydroxyl groups and unsaturation in the aromatic benzene ring [165]. A thiolactone analog of AHL covalently linked to ciprofloxacin (QS0108) (**13**) was developed by [PERSON] et al. to assess them as inhibitors of AHL-2 in _P. aeruginosa_. This system effectively disrupted dormant and mature biofilms compared to antibiotic treatment alone (Figure 8) [166].