**2.3 Biofilm inhibition and eradication**

*Microorganisms*

subsequent PQS cascade [11].

none ω-hydroxyemodin as inhibitor of AgrA [78].

**2.2 Control of the global regulators**

promoters of target genes [85, 86].

structure [79].

including S-phenyl-l-cysteine sulfoxide and diphenyl disulfide [66] and tetrazole derivatives [67]. Furthermore, synthetic LasR derivatives have been developed such as indole derivatives, non-AHL-like antagonists [68], the synthesized azines derivatives, 4-(alkyloxy)-6-methyl-2H-pyran-2-one [69] and aspirin [70]. Triphenyl hybridγ-butyrolactones and cyclopentanones derivatives are potent inhibitors of LuxR [71]. Putative LasI inhibitors have been identified using molecular docking methods including the trans-cinnamaldehyde [72], (z)-5-octylidenethiazolidine-2, 4-dione [73] and fatty acyl purified from marine *Streptomyces* sp. [74]. Additionally, meta-bromo-thiolactone is a potent inhibitor of RhiI and

In *S. aureus*, the interference with agr system has been accomplished using solonamide A and B that are cyclodepsipeptides derivatives, which purified from marine *Photobacterium* and reduced the expression of *hla* and RNAIII. Solonamide can act through competitive inhibition of agr system such as *S. aureus* agr system via structure similarity to the AIPs [75]. Other *S. aureus* quorum-sensing inhibitors have been identified including linear peptidomimetics as competitive inhibitors to AgrC [76], savirin as potent inhibitor of AgrA [77] and the polyhydroxy anthraqui-

Beside the QS regulons, other global regulators exhibit crucial functions in dominating the expression of various genes in assortment style as a response to environmental stimuli and changes, most notably the temperature change [5]. These so-called global regulators enable the bacterial communities to survive different environmental stresses including starvations, pH changes and temperature fluctuations, through the quick conformation of bacterial physiology and

Among many regulators that coordinate gene expression in bacteria, in Gramnegative bacteria, the global regulator termed histone-like nucleoid-structuring (H-NS) protein is relatively significant and of paramount importance [80]. H-NS has been considered as the main model of studying how global regulators can affect bacterial structure and physiology. The H-NS protein is incorporated in the regulation of many genes responsible for controlling the physiological functions of Gram-negative bacterial cells involving cellular functions, survival under different environmental conditions and production of various virulence factors [81, 82]. Moreover, in Gram-positive bacteria, there are several global regulatory loci [83]. Among them in the *S. aureus*, SarA, a regulatory DNA binding protein involved in controlling the virulence genes expression, is well documented [84]. During regulation of the expression of various genes, these regulators have been demonstrated to act either as a positive regulators through enhancing the stability of the mRNA of expressed genes, resulting in excessive translation, or as a silencer protein that alter and decrease the gene expression by hindering binding of RNA polymerases to the

This would open up novel approaches for the treatment and eradication of pathogenic bacteria utilizing inhibitors or modulators of these global loci to vanquish the global concerns of antimicrobial resistance and immune evasion of microbial pathogens. Among these approaches, the interesting inhibitor of SarA (SarABI), 4-[(2,4-diflurobenzyl)amino] cyclohexanol, was confirmed as SarAbased new curative medicament against *S. aureus*-related infections [87]. This might encourage research groups for screening other compounds that might affect global regulators in bacteria to give a new therapy for multi-drug resistant (MDR) bacte-

**196**

rial strains.

Biofilm is a sessile community of microbial cells that is found to be attached to animate or inanimate surface, and usually surrounded by a matrix of polysaccharides, proteins and DNA [6]. The cells in these sessile communities differs phenotypically form those present in planktonic communities [88]. Bacterial cells in planktonic forms are almost one thousand times more sensitive to antibiotics than their biofilm counterparts [7]. Additionally, biofilms act as a defense mechanism against different stress conditions or immune cells attack [89].

In this part, we will focus on the agents that are known to exhibit antibiofilm activity.
