## 4 Antimicrobial Agents
### Synthetic Small Organic Molecules  
The design of synthetic small organic molecules has paved a new route to overcome antibiotic tolerance and interfere with biofilms [78]. It has drawn remarkable attention in the past few decades. Numerous research shows that small organic molecules inhibit biofilms by different modes of action (Table 4). \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Compound/Molecule** & **Mode of Action** & **Effective Against** & **Reference** \\ \hline Garlic extracts & inhibits QS & _P. aeruginosa_ & [62] \\ \hline Garlic extracts & inhibit LasR and LuxR & _P. aeruginosa_ & [63] \\ \hline Isolimonic acid & cell-cell signaling & _E. coli_ & [64; 65] \\ \hline Isolimonic acid & reduce LuxR DNA binding & _Vibrio_ spp. & [65] \\ \hline Cinnamaldehyde & swimming motility & _E. coli_ & [66] \\ \hline \multirow{2}{*}{Hordenine} & decrease in signaling molecule, inhibition of & _P. aeruginosa_ & [67; 68] \\  & QS-related genes & _P. aeruginosa_ & [67; 68] \\ \hline Autoinducing peptide type I (AIP-I) & inhibit QS & _S. aureus_ & [74] \\ \hline RNAIII-inhibiting peptide (RIP) & inhibit QS & _S. aureus_ & [75] \\ \hline Querentin & decrease LasI/R, Rhl/R expressions & _P. aeruginosa_ & [73] \\ \hline \hline \end{tabular}
\end{table} 
Table 3: Natural compounds as antiquorum sensing molecules in biofilm dispersal. Some imidazole and benzimidazole compounds are able not only to inhibit biofilms but also to disperse them. The molecular mechanism behind the antib biofilm effect for the 5-phenyl-2-aminoimidazole was interpreted in _Salmonella typhimurium_[79]. The study emphasizes the potential of 5-phenyl-2-aminoimidazole to decrease the expression of CsgD, and adrA and csgB genes regulated by it, thus preventing the biofilm EPS formation [79]. [PERSON] et al. synthesized a 5-methoxy-2-[(4-methyl-benzyl) sulfanyll-1H-benzimidazole, commonly known as ABC-1 (antibiofilm compound-1) which showed an antib biofilm effect against the Gram-negative bacteria _Vibrio cholera_ and _P. aeruginosa_[80]. ABC-1 was also able to inhibit biofilms in Gram-positive pathogens including _S. aureus_ at lower concentrations by targeting eDNA, polysaccharide intercellular adhesion (PIA), and Protein A (SpA) expression [1]. Likewise, [PERSON] et al. confirmed the strong effect of the 5, 6-dimethoxy-2-aminobenzimidazole not only inhibited _P. aeruginosa_ biofilms but also dispersed them by targeting two QS receptors, LasR and RhlR [81]. Pyrazole is an exceptional aromatic heterocyclic compound with five-membered rings, is also known to be a biofilm modulator. [PERSON] et al. tested three Pyrazolo-pyrimido [4,5-d] pyrimidines (compounds 19 a-c) and found that it was able to inhibit Gram-positive bacteria including _S. aureus_, _B. subtilis_, and _Microococcus luteus_[82]. Remarkably, biofilm treatment with compound 19b displayed a substantial surge in intracellular ROS levels in _M. luteus_ at the dose of 0.5 \(\mu\)g/mL, which caused the cells to undergo oxidative stress that caused membrane damage leading to cell lysis and death [83,84]. Indole derivatives are known to repress motility, chemotaxis, and adhesion in _E. coli_. In a screening of six plant and animal derivatives of indole, indole-3-carboxylaldehyde and 3-indolylacetonitrile were found to be potential biofilm inhibitors against _P. aeruginosa_ and _E. coli_ O157: H7. These compounds decrease biofilms by reducing curli production without affecting microbial growth [85,86]. 2-Phenylhydrazineylidene derivatives can prevent bacterial adhesion by Sortase A (StrA) inhibition [87], a transpeptidase enzyme that aids in biofilm production by incorporating cell-surface proteins into the Gram-positive bacteria cell wall. Inhibition of StrA is also associated with loss of virulence factors in _S. aureus_, including attenuation in the binding potential to fibrinogen, and fibronectin, IgG, along with a decrease in biofilm formation [88,89,89]. Pyrrole derivatives are also found to inhibit biofilms in Gram-positive pathogens.