# Development of Antibiofilm Therapeutics Strategies to Overcome Antimicrobial Drug Resistance
## 5 Emerging Antibiofilm Agents
### Quaternary Ammonium Compounds  
QACs represent a class of broad-spectrum antimicrobials possessing a central amphiphilic core and a lipophilic alkyl side chain linked to a hydrophilic quaternary ammonium framework. Although QACs imitate the action of the AMPs they have a comparatively simplified structure. The mode of action of these agents as antimicrobials is by cleavage  
Figure 9: Chemical structures of some enzymatic cleavage inhibitors.  
of the cell membrane, which consequently leads to nutrient leakage followed by cell lysis and death. Although, this class of compounds have already been established as disinfectants, antiseptics and preservatives their role as antibiofilm agents has only recently been recognised.  
In a study by [PERSON] et al. two quaternary ammonium methacrylate (QAM) derivatives, dimethylaminododecyl methacrylate (DMADDM) (**20**) and dimethylamino-hexadecyl methacrylate (DMAHDM) (**21**), were designed and evaluated for their efficacy as antibiofilm agents against _E. faecalis, Streptococcus gordonii, Actinomyces naeslundii,_ and _Lactobacillus acidophilus_ using chlorhexidine and sodium hypochlorite as standards. In particular, the minimal biofilm inhibitory concentration (MBIC) for DMADDM and DMAHDM against a combination of four endodontic bacteria was 25 \(\upmu\)g/mL and 6.25 \(\upmu\)g/mL, respectively [190]. [PERSON] et al. investigated quaternary ammonium silanes (QASs) (**22**) as biofilm disruptors by exposing them to _S. mutans_ and _L. acidophilus_ preformed biofilms over dentine disks, at different concentrations. Inhibition of enzyme StrA, responsible for the adhesion of proteins onto the cell membrane and connecting the proteins to form pili, was studied at a concentration of 2% QAS dilution and exhibited significant reduction with an IC50 value of 3.3 \(\pm\) 2.7 \(\upmu\)M, a more potent value as compared to polyhexamethylene biquanide taken as positive control, IC50 = 24.5 \(\pm\) 4.1 \(\upmu\)M [191].  
In a study conducted by [PERSON] et al., two distinct QACs having a dicationic porphyrin core, XF-70 (**23a**) and XF-73 (**23b**), were evaluated for their disruption of _S. aureus_ biofilms. Both analogues entirely disrupted preformed _S. aureus_ biofilms at a concentration of 2.6 \(\upmu\)M [192; 193]. The analogue XF-73 is currently being developed as a topical preparation by Destiny Pharma (Brighton, UK) and has started with a phase-II trial to assess its effect on patients with post surgical Staphylococcus nasal infestation. A phase-I trial of XF-73 has shown noteworthy positive results [194]. [PERSON] et al. evaluated the effectiveness of 4.4\({}^{\prime}\)-(\(\upalpha\),\(\upomega\)-hexamethylenedithio) bis (1-octylpyridinium bromide) (4 DTBP-6,8) commonly known as gemini QACs a seventh generation BisQACs as an antibacterial and antibiofilm agent towards _P. aeruginosa_. A susceptibility assay for biofilm cells was performed which  
Figure 10: Chemical structures of some efflux pumps inhibitors.  
showed the numbers of surviving cells with cetylpyridinium chloride and benzalkonium chloride used as reference was 984- and 186- fold higher compared to cells treated with 4 DTBP-6,8 (**24**) (Figure 11) [195].