# Strategies to Combat Multidrug-Resistant and Persistent Infectious Diseases
## 2 New Anti-Infectious Treatments against MDR and Persistent Bacteria
### Antimicrobial Peptides (AMPs)  
Antimicrobial peptides (AMPs) are currently being studied and developed for the treatment of recalcitrant bacterial infections, which are often caused by persistent bacteria. In relation to this relatively new therapy, the synergistic interactions between AMPs and antibiotics together with the anti-biofilm activity of AMPs are of great interest. Many AMPs are produced naturally by a broad range of organisms, while others are designed and chemically synthesized in the laboratory.  
In a recent study, [PERSON] and colleagues characterized nine fungal defensin-like peptides, i.e., peptides synthesized by neutrophils with antimicrobial and cytotoxic properties, and identified them as potent antibacterial compounds [31]. The peptides were expressed in _Pichia pastoris_, and their antibacterial and anti-biofilm activities against MDR and persistent _S. aureus_ were evaluated. The study findings showed that a defensin-like peptide called P2 exhibited the highest activity and expression level with low toxicity, no resistance, high stability, and a MIC of \(<\)2 ug/mL. P2 bound to bacterial DNA, wrinkled the outer membrane, permeabilized the cytoplasmic membrane, and inhibited _S. aureus_ biofilm formation. Importantly, P2 killed 99% of persistent bacteria, which were resistant to 100\(\times\) MIC of vancomycin. These data suggest that P2 may be a candidate in the development of novel antimicrobial agents against MDR and persistent staphylococcal infections.  
[PERSON] and colleagues characterized two novel peptides, P5 (YIRKIRFFKKKLKKILKK-NH2) and P9 (SYERKINRHFKTLKKNLKKK-NH2), which exhibit potent antimicrobial activities against both methicillin-sensitive _S. aureus_ clinical isolates and methicillin-resistant _S. aureus_ (MRSA) strains [32]. As previously described for P2, these peptides did not cause significant hemolysis or cytotoxicity to renal epithelial cells. P5 and P9 significantly inhibited the _S. aureus_ biofilm and disrupted the cell membrane, in addition to downregulating several virulence genes. P5 and P9 may, therefore, be promising antibacterial agents for the treatment of MRSA infections.  
In 2019, [PERSON] and colleagues investigated the potential applications of cationic peptides in the fight against vancomycin-resistant _Enterococcus_ (VRE) [33] and found some peptides displaying moderate bactericidal activity against VRE, with MIC values of 2-8 ug/mL, as well as significant synergistic interactions between these peptides and vancomycin. The mechanism of action of these peptides is the inhibition of _vanRS_ transcription, a key two-component system (TCS) in the resistance against vancomycin. These researchers showed that inhibition of _vanRS_ transcription restored vancomycin activity. Consistent with in vitro results, the researchers observed higher survival rates in _Galeria mellonella_ larvae treated with these cationic peptides plus vancomycin than in larvae treated with vancomycin alone. Together, these results suggest that cationic peptides show antibacterial activity against VRE and also reverse vancomycin resistance in _Enterococcus_, and they are, therefore, promising candidates for combating vancomycin-resistant pathogens.