# Strategies to Combat Multidrug-Resistant and Persistent Infectious Diseases
## 4 Discussion  
Bacterial infections account for millions of deaths annually worldwide and, among these, persistent infections have a large clinical impact. Persistent cells are one of the main causes of such recurring infections [86]. As stated above, persistence to antibiotics is not always due to genetic changes and can be caused by metabolic inactivity and dormancy, strictly regulated by complex molecular processes such as the (p)ppGpp network, QS, or toxin-antitoxin (TA) systems, all of which were recently reviewed by [PERSON] and colleagues [23]. Strategies for avoiding antibiotic therapy failure usually focus on genetic resistance, while other bacterial survival strategies, such as persistence or tolerance to antibiotics, are increasing. A closer look at such strategies is necessary in order to combat persistent and re-incident bacterial infections caused by resistant pathogens. In an interesting recent review, [PERSON] and colleagues examined some of the new treatments summarized in the present review, together with vaccines and immune-modulator-based therapies [87]. In the present review, we focused first on new treatments (antimicrobial peptides, anti-virulence strategies, phage-based therapies, and new molecules) and then on drug repurposing assays (anti-inflammatory and anti-psychotic compounds, anti-helmthics, anti-cancerous drugs, and statins). Antimicrobial peptides open a huge spectrum of possibilities as they are less prone to generating resistance than antibiotics and they can be chemically modified to enhance their antibacterial activity. We mentioned two of these (Table 1), but the mechanisms of action of several AMPs currently being investigated were reviewed by [PERSON] and colleagues, which basically involve interference of the membrane or disruption of cellular processes [88]. [PERSON] and colleagues also conducted an exhaustive review of the advances regarding AMPs [89] and reported that 20 AMPs are currently being tested in clinical trials, ranging from preclinical stage to phase III, mostly, although not exclusively, for topical indications. The vast majority of these compounds are cyclic polycatonic peptides. Focusing on anti-virulence strategies, we included here QS inhibitors, inhibitors of global virulence regulators, and pump-efflux inhibitors, as well as a ClpP protease activator. Much information about these anti-virulent compounds was provided in an exhaustive review conducted by [PERSON] and colleagues [90]. Similarly, [PERSON] and colleagues conducted a detailed analysis of 26 patents of anti-virulence compounds published between 1994 and 2012 [91]. These compounds included some inhibitors of adhesion and colonization, secretion systems, or cellular signaling systems, among other virulence factors. The large number of patents produced in less than two decades reflects the increasing interest in anti-virulence compounds and their antibacterial properties. Regarding bacteriophages or their components (e.g., endolysins, reviewed in the text), in Western countries, there are regulatory hurdles and legal problems associated with the use and administration of viruses as clinical tools. The factors leading to the controversy surrounding the clinical use of using phages as antimicrobial agents include the complicated regulatory issues, safety concerns, and skepticism about their therapeutic efficacy, e.g., because of the evolution of phage resistance. To date, only nine trials using phage therapy were conducted [92]. As suggested by [PERSON] in 2018, the choice of appropriate targets is an important factor to consider as the high species specificity of phages may be desirable in monomicrobial infections but can limit polymicrobial infections [93]. Phage-antibiotic synergy (PAS) was demonstrated both in vitro and in vivo [94] and, even when no benefits were obtained, the emergence of antibiotic- or phage-resistant phenotypes was greatly minimized.