# Strategies to Combat Multidrug-Resistant and Persistent Infectious Diseases
## 3 Repurposing Treatments against MDR and Persistent Bacteria
### Statins  
Statins are lipid-lowering molecules with pleiotropic effects, and their potential antibacterial ability was reported. In 2008, [PERSON] and [PERSON] observed that some statins directly inhibited the growth of species belonging to the genera _Staphylococcus_, _Streptococcus_, _Enterococcus_, and _Moraxella_, thus indicating some possible antimicrobial activity of the drugs [80]. In humans, statins inhibit the enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA) leading to decreased synthesis of cholesterol and increased removal of low-density lipoprotein (LDL) circulating in the body [81]. [PERSON] and colleagues evaluated the antibacterial activity of simvastatin, and they observed no synergistic interactions between the statin and vancomycin [82]. However, simvastatin was able to reduce the formation and viability of mature biofilms, decreasing cell viability and extra-polysaccharide production. Simvastatin also caused a significant decrease in _M. tuberculosis_ bacterial load, presumably by reducing cholesterol synthesis due to the inhibition of HMG-CoA reductase within the phagosomal membrane (reviewed in Reference [83]). Using a murine MRSA skin infection model, [PERSON] and colleagues confirmed that simvastatin significantly reduced the bacterial burden in infected wounds, displaying excellent anti-biofilm activity against established staphylococcal biofilms in vivo [84]. Considered together, these findings suggest the potential bactericidal activity of simvastatin alone or in combination with topical antimicrobials currently used to treat MRSA skin infections. The in vitro antibacterial effects of statins against skin pathogens such as _S. aureus_, _E. coli_, _P. aeruginosa_, and _Serratia marcescens_ were verified in a recent study [85]. Tables 1 and 2 respectively summarize the anti-MDR bacteria and anti-persister treatments described above. \begin{table}
\begin{tabular}{c c c c c} \hline \hline
**Name of Drug** & **Type of Drug** & **Active against** & **Mechanism of Action** & **Reference** \\ \hline P5 and P9 & AMPs & MRSA & Inhibition of biofilm, disruption of membrane integrity, downregulation of virulence genes & [32] \\ \hline Cationic peptides & Inhibition of TCS \(unRS\) & VRE & Restoration of vancomycin activity & [33] \\ \hline Inhibitors of AcrAB-ToC & Inhibition of AcrAB-ToC & MDR _Escherichia coli_ & \begin{tabular}{c} Restoration of antibiotic activity, induction of spontaneous mutations, inhibition of DNA mismatch repair system \\ \end{tabular} & [37] \\ \hline Cocktail of 9 lytic phages & Lytic phages & MDR _Acinetobacter humammii_ & Lysis of MDR _A. humammii_ cells & [43] \\ \hline Ab105-2 phiACI & Engineered phage & MDR _A. humammii_ & Lysis of MDR _A. humammii_ cells, synergy & [49] \\ \hline LysAB2 & Endolysin from a phage & MRSA & \
\begin{tabular}{c} Bactericidal activity against MRSA, _A._ \\ _humaniii_, and _E. coli_ \\ \end{tabular} & [54] \\ \hline Cbf-K\({}_{16}\) & AMP anti-inflammatory & Clarithromycin and amoxicillin-resistant & Inhibition of IL-8, downregulation of virulence and adhesion genes & [61] \\ \hline
\begin{tabular}{c} 5-Fluorouracil and \\ 6-thioguanine \\ \end{tabular} & Anti-cancerous & _A. humammii_ & Pirimidin and purin analogues & [73] \\ \hline Gallium & Anti-cancerous & MDR ESAPE & Competition with Fe\({}^{*3}\) & [76] \\ \hline Clomiphene & Anti-cancerous (SEM) & MRSA & Inhibition of UPPS, synergy with \(\beta\)-lactams & [79] \\ \hline Simvastatin & Statin & MRSA skin infections & Anti-biofilm activity against staphylococcal biofilms in vivo & [84] \\ \hline \hline \end{tabular}  
* AMP: antimicrobial peptides; MRSA: methicillin-resistant S. aureus; TCS two component system; VRE: vancomycin-resistant _Entroexcts_; MDR: multi-drug resistant; ESAPE: _E. fraction_, _S. aureus, K. pneumoniae, A. humammii, P. aeruginosa, Entributor \(\varphi\)_; SERM selective estrogen receptor modulator  
\end{table} 
Table 1: Anti-multidrug-resistance (MDR) molecules that show activity against multidrug-resistant bacteria.