**Abstract**

Different institutions recognized that antimicrobial resistance is a global health threat that has compounded by the reduction in the discovery and development of new antimicrobial agents. Therefore, the development of new antimicrobial therapeutic strategies requires immediate attention to avoid the 10 million deaths predicted to occur by 2050 as a result of multidrug-resistant (MDR) bacteria. Despite the great interest in the development of repurposing drugs, only few repurposing drugs are under clinical development against Gram-negative criticalpriority pathogens. In this chapter, we aim: (i) to discuss the therapeutic potential of the repurposing drugs for treating MDR bacterial infections, (ii) to summarize their mechanism of action, and (iii) to provide an overview for their preclinical and clinical development against these critical-priority pathogens.

**Keywords:** repurposing drug, infection, bacteria, nosocomial, clinical

### **1. Introduction**

Antimicrobial resistance poses a well-recognized global health threat due to the global dissemination of bacteria resistants to multiple antibiotic classes. This situation is deemed a global priority by the World Health Organization and the European Centre for Disease Prevention and Control [1, 2]. Currently, global deaths due to antimicrobial resistance are more than 70,000 in USA and in Europe together [3, 4]. Therefore, the development of new antimicrobial therapeutic strategies requires immediate attention to avoid the high number of deaths predicted to occur in the future as a result of multidrug-resistant (MDR) bacteria [5]. It is clear that effective solutions such as the establishment of antimicrobial stewardship programs to optimize the use of existing antibiotics, the promotion of novel rapid diagnostics to curtail the unnecessary use of antimicrobial agents; the promotion, development, and use of vaccines and novel antibiotic classes are urgently needed [5]. However, the increased prevalence of infections by MDR bacteria and the scarcity of novel antibiotic families that are under clinical development could warrant the development of new antimicrobial therapeutic strategies for use alone or together with one of the scarce but clinically relevant antibiotics.

Repurposing drugs have been gained renewed interest in the last decade as reflected by several recent studies [6–9]. Since then, 4% of the 407 preclinical antibiotic projects from 314 institutions are related with repurposing drugs evaluated against bacterial infections [10]. Further evidence of the increased interest in these drugs class is that the development process for repurposed drugs benefits from a large body of available knowledge and reduces the time and cost of development [9]. The majority of repurposed drugs developed to treat bacterial infections are approved or in advanced clinical stages as anticancer drugs, anti-inflammatory/ immunomodulatory drugs, antipsychotic and antidepressant drugs, statins and iron-storage drugs [9]. The large difference between the numerous drugs approved or in development for oncologic indications and the small number of new antibiotics is surprising given that over the past decades antimicrobial resistance has emerged as an important public health with high associated mortality, and in 2050 antimicrobial resistance would result in 10 million more deaths than those caused by cancers [5]. Although multiple factors contribute to the scarcity of new antibiotics for bacterial infections, the success of repurposing drugs-based antibiotic therapy as an alternative approach can be reached. Repurposing drugs-based approaches could provide a viable alternative for the treatment of certain MDR bacterial infections. This could be especially important for certain infections caused by MDR Gram-negative infections such as *Acinetobacter baumannii, Pseudomonas aeruginosa* and *Enterobacterales* carbapenems-resistants, for which current antimicrobial treatments are not active. The WHO has classified as critical priority these pathogens for research and development of new antibiotics [1].

In this chapter, we focus on the current state of knowledge regarding the potential benefits and disadvantages of repurposing drugs treatments for MDR Gram-negative infections. We outline the advances to-date in their preclinical and clinical development as antimicrobial agents. To this end, we introduce in Pubmed database different key words such as repurposing drug, repositioning, antimicrobial and/or antibacterial in order to find published literature about the repurposing drugs for treatment of bacterial infections.
