# Strategies to Combat Multidrug-Resistant and Persistent Infectious Diseases
## 3 Repurposing Treatments against MDR and Persistent Bacteria
### Anti-Cancerous Drugs as Antibacterialers  
The use of anti-cancer agents to treat bacterial pathogens may appear surprising. However, although cancer and infectious diseases differ in many aspects, drug-tolerant persisters also occur in cancer cell populations and are implicated in the recurrence of tumors.  
[PERSON] and colleagues recently used an _A. baumannii_ strain resistant to most antibiotics (AB5075) and reported that three antineoplastics (5-fluorouracilacil, 6-thioguanine, and pifithrin-\(\upmu\)), an anti-rheumatic (auranofin), an antipsychotic (fluspirilene), an anti-inflammatory (Bay 11-7082) and an alcohol detergent (disulfram) inhibited the growth of MDR _A. baumannii_[73]. The best candidates among all the repurposed drugs in the treatment of MDR clinical _A. baumannii_ appeared to be 5-fluorouracilacil and 6-thioguanine, as the inhibitory concentration 90 (IC\({}_{90}\)) values and MIC were lower than standard plasma drug concentration levels in human, suggesting possible use without major adverse events. The authors hypothesized that 5-fluorouracilacil may display the same inhibitory mechanism against bacterial pathogens as against tumor cells, by inhibiting thymidylate synthase. Similarly, 6-thioguanine may also share its mechanism of action against tumor cells and bacteria, as it works as a guanine analogue, disrupting DNA and RNA synthesis.  
The antibacterial activity of the metal gallium is known for more than 80 years. Due to its chemical similarity to iron, gallium inhibits ferric redox reactions or pathways affecting bacterial growth. Gallium has a broad spectrum of activity, particularly against MDR ESKAPE pathogens [74; 75]. In fact, the activity of gallium was assessed in a phase 2 trial in cystic fibrosis _P. aeruginosa_-infected patients [76], providing evidence of its safety and efficacy for human infections, improving pulmonary capacity without affecting the activity of essential human enzymes, such as superoxide dismutase and aconitase.  
Mitomycin C is also known to induce DNA cross-linking in a growth-independent manner, killing persisters and actively growing cells of several pathogens such as _E. coli_, _S. aureus_, and _P. aeruginosa_[77]. However, [PERSON] and colleagues claimed that the anti-cancer drug cisplatin forms intra-strand DNA cross-links and, therefore, eradicates _E. coli_ K-12, _S. aureus_, and _P. aeruginosa_ persister cells througha growth-independent mechanism and more efficiently than mitomycin C, which forms inter-strand DNA cross-links [78].  
Finally, hormonal modulators used as anti-cancerous agents also play a role in the fight against resistant bacterial populations. Selective estrogen receptor modulators (SERMs) are widely used to treat breast cancer. These drugs include clomiphene, currently under preclinical development for fertility treatment [79]. Clomiphene displays in vitro activity against _S. aureus_, with an MIC value of 8 mg/L. It acts by inhibiting undecaprenyl diphosphate synthase (UPPS), an enzyme involved in the synthesis of teichoic and peptidoglycan of the _S. aureus_ cell wall. It was also reported that, due to its mode of action, clomiphene interacts synergistically with \(\beta\)-lactams in restoring MRSA susceptibility [79].