# Strategies to Combat Multidrug-Resistant and Persistent Infectious Diseases
## 1 Introduction  
Antimicrobial resistance is currently considered one of the principal threats to global public health by the World Health Organization (WHO) [1], especially because of the global spread of multidrug-resistant (MDR) bacterial pathogens. MDR pathogens can develop resistance to different antimicrobials via horizontal gene transfer and via gene mutations as a consequence of exposure to these drugs. Although the acquisition of resistance is a natural process, it is exacerbated by the misuse of antibiotics, inadequate surveillance, and the poorly controlled regulation of antibiotics in clinical medicine and in the livestock industry, which led to the appearance and spread of MDR bacteria all over the world [1; 2; 3]. Mortality caused by resistance to antibiotics is a major health problem, causing more than 23,000 deaths a year in the United States (US) alone (Center for Disease Control, Antibiotic Resistance Threats in the United States, 2019 (2019 Antibiotic Resistance Threats Report)) and more than 33,000 in Europe [4]. Already alarming, the number of deaths is predicted to increase worldwide to more than 10 million by 2050, although predictions are difficult to make in this field [5; 6]. In 2008, [PERSON] and colleagues first referred to the six most frequent MDR bacterial pathogens, i.e., _Enterococcus faecium_, _Staphylococcus aureus_, _Klebsiella pneumoniae_, _Acinetobacter baumaniii_, _Pseudomonas aeruginosa_, and _Enterobacter_ spp., as the \"ESKAPE\" pathogens [7]. Some other opportunistic pathogens, such as _Escherichia coli_, _Enterococcus faecalis_, and _Burkholderia cepacia_ can also become MDR strains and are able to cause severe infections. Bacteria can evade the antimicrobial activity of antibiotics via three different but related mechanisms: resistance, tolerance, and persistence [8]. Resistance is the ability of bacteria to grow in the presence of high concentrations of an antibiotic and is caused by inherited mutations, which affect the efflux pumps, the drug target, or the antibiotic molecule itself [8; 9]. Resistant populations can be found in all types of environments: water, animals, inanimate surfaces, humans, plants, and food [10; 11; 12; 13]. Moreover, resistant bacteria can grow under antibiotic pressure, their resistant phenotype is inheritable, and a significant increase in the minimal inhibitory concentration (MIC) of antibiotics is required to effectively kill them [14]. However, resistance phenotypes are not always due to the acquisition of resistance genes or mutations in the bacterial genome, and they can often explained by the appearance of a persistent phenotype, which includes tolerant populations of bacteria and/or the presence of persistent sub-populations (known as \"persister cells\" or \"persisters\") within a population of susceptible cells (i.e., killed by an antibiotic at a concentration equal to or lower than the MIC). Bacteria exhibiting this persistent phenotype are able to overcome antibiotic treatment but do not affect the MICs of the drugs. As with resistance, tolerance and persistence were first observed shortly after the introduction of penicillin, as reviewed very recently by [PERSON] and colleagues [15]. Antibiotics then become ineffective owing to the lack of cellular metabolism and to the effect on or interference in DNA replication, transcription, and translation, as well as cell-wall synthesis. \"Persisters\" are non-growing, metabolically inactive, dormant bacteria that exhibit transient high levels of tolerance to antibiotics and play a non-negligible role in chronic or recurrent infections [14], as they can survive both antibiotic therapy and host immune responses. The dormant bacteria can rapidly revert to the wild-type (WT) phenotype and regain their antibiotic susceptibility when drug pressure is removed and their metabolic activity is reactivated. The signaling pathways involved in this \"awaking\" process are being further investigated [16; 17].