# The Complex Relationship between Virulence and Antibiotic Resistance
## 4 Regulation of Virulence and Antibiotic Resistance
### Transcription Factors  
Transcription factors can regulate gene expression directly or indirectly through global gene regulators in both virulence and antibiotic resistance genes. Regulation of virulence genes where the transcription factors bind directly to the promoter region has been seen in Enterohemorrhagic _Escherichia coli_ (EHEC) where the transcription factors Cra, KdpE, and FusR bind directly to the _ler_ region on the locus of enterocyte effacement (LEE) pathogenicity island in order to control the gene expression [145]. The global transcriptional regulator H-NS, has been shown that EHEC _hns_ deletion mutants showed lower survival rates and a higher bacterial burden in the gut of infected BALB/c mice. In comparison the wild type EHEC strains were more virulent and had a higher ability to colonize the gut of the infected BALB/c mice, this was found to be especially true when antibiotics were not administered, leading to the conclusion that H-NS interacts with the gut microbiota of the mice in order to cause virulence [146]. Alternatively, PrfA, a member of the cyclic AMP transcriptional regulators that appears to be a master virulence regulator in _Listeria monocytogenes_ as it binds DNA as dimers in gene promoters to activate transcription [147].  
Regulation of antibiotic resistance genes through transcription factors have been observed in methicillin resistant _S. aureus_ (MRSA), particularly strains with intermediate level resistance to vancomycin (VISA). VISA is facilitated by the transcription factors _yvcH_ and _yycI_, which was shown to down-regulate the two-component regulator WalRK when the two genes were knocked out. Additionally, down-regulation of the cell wall hydrolase genes _altA_ and _sle1_ was seen to cause impaired autolytic function of the deletion mutants when compared to the wildtype. This reduction in WalRK expression leads to decreased ability for cell wall turnover, which ultimately leads to a decreased effect of vancomycin [148]. Another example is the identification of Ms4022 a novel TetR transcriptional regulator in _Mycobacterium smegmatis_ has been shown to activate the expression of several transport drugs that have affects the strains resistance to drugs. When Ms4022 was overexpressed in the wildtype strain of _M. smegmatis_, its growth was inhibited, but the strain's resistance to the anti-tuberculosis drug rifampicin was enhanced. Alternatively, deletion of Ms4022 showed an increased susceptibility to the drug rifampicin. Ms4022 was found to directly regulate seven transport related genes that are thought to result in the resistance this strain has for rifampicin [149]. Several other genetic regulators--_relA_, _spot_, _brlR_, and _crc_ (catabolite repression regulator) have been investigated to increase antibiotic tolerance in _P. aeruginosa_ in response to either ciprofloxacin or tobramycin [150; 151]. Other regulatory genes fall in the oxidative stress, hypoxia (i.e., Anr regulon), osmotic stress, growth arrest (RpoS), and quorum sensing pathways, which have been shown to play a role in antibiotic sensitivity [150]. The precise transcriptional regulation of antibiotic resistance is also dependent on the type of antibiotic.