**2. Therapeutic potential of repurposing drugs**

There is a widely acknowledged that repurposing drugs could address the global increase in antimicrobial resistance and especially the treatment of MDR Gram-negative bacteria. This could be due by the fact that repurposing drugs might exhibit some advantageous characteristics. Repurposing drugs target some genes and surface proteins that are not targets of currently used antimicrobials [9]. Of note, it is unlikely that their antibacterial activities can be disturbed by existing antimicrobial resistance mechanisms. The most of repurposing drugs increased the permeability and damaged the bacterial membrane without killing the bacteria. They enhanced the activity of the current antibiotics [9]. Furthermore, repurposing drugs are drugs approved by the Federal Drug Administration (FDA), information about their pharmacological characteristics (both safety and pharmacokinetic) in preclinical and clinical trials is widely available. Therefore, the time and economic costs associated with the repurposing of these drugs for other therapeutic applications such as the treatment of bacterial infections will be minimized [11]. Finally, to our knowledge, it was not reported that repurposing drugs produce selective pressure on the human microbiome.

Substantial progress has been made in the development of repurposed drugs against bacterial infections. Although some current compounds in the pipeline have exhibited promising results, existing pharmacokinetic characteristics limits the activity of many of them. It should be taken into account in the preclinical development of repurposing drugs the possible need for new formulations to increase

**99**

**Figure 1.**

*Drugs Repurposing for Multi-Drug Resistant Bacterial Infections*

their bioavailability and absorption. This aspect is relevant for the development of anthelmintics. Extensive binding to plasma proteins has been reported for oxyclozanide and other salicylanilides, which currently limits their systemic and intravenous applications [12]. Of note, positive results have been seen with niclosamide derivative O-alkylamino-tethered, which has a potent antibacterial effect against carbapenemase producing and colistin resistant *Enterobacterales* isolates [13]. Inhalable nanosuspension and salt form of niclosamide, niclosamide ethanolamine, have presented better solubility profile and inhibited the *P. aeruginosa* quorum sensing (QS) [14, 15]. An additional relevant issue should be taken into account is that their administration route can be changed. ADMET tests should be performed before the development of these repurposing drugs in clinical trials. The choice of the route is a relevant aspect in serious infections in hospitalized patients such as ventilated-associated pneumonia who patients are intubated and other circum-

**3. Mechanisms of action of repurposing drugs against Gram-negative** 

*nosa* and *Enterobacterales*) are summarized in **Figure 1** and **Table 1**.

*Mechanisms of action of repurposed drugs against Gram-negative critical-priority pathogens.*

Different agents are promising both in vitro and in vivo candidates to be repositioned as antimicrobial agents to treat infections caused by MDR Gram-negative bacilli. A variety of drugs with different mechanisms of action and targets have been selected including: DNA, RNA and proteins inhibitors [16–20], QS regulators [15, 17, 21–25], biofilm formation inhibitors and disruptors [26, 27], drugs that interact with cell membrane [28–30], drugs that interact with iron metabolism [31–35], and host immune system modulators [36–39]. These drugs and their mechanisms of action against critical-priority pathogens (*A. baumannii*, *P. aerugi-*

Anticancer and anti-inflammatory drugs that interact with DNA, RNA and proteins have been reported. Mitomycin C, used in several types of carcinomas such

*DOI: http://dx.doi.org/10.5772/intechopen.93635*

stances in which the oral route is not available.

**3.1 DNA, RNA and proteins inhibitors**

**bacilli**

*Drugs Repurposing for Multi-Drug Resistant Bacterial Infections DOI: http://dx.doi.org/10.5772/intechopen.93635*

their bioavailability and absorption. This aspect is relevant for the development of anthelmintics. Extensive binding to plasma proteins has been reported for oxyclozanide and other salicylanilides, which currently limits their systemic and intravenous applications [12]. Of note, positive results have been seen with niclosamide derivative O-alkylamino-tethered, which has a potent antibacterial effect against carbapenemase producing and colistin resistant *Enterobacterales* isolates [13]. Inhalable nanosuspension and salt form of niclosamide, niclosamide ethanolamine, have presented better solubility profile and inhibited the *P. aeruginosa* quorum sensing (QS) [14, 15]. An additional relevant issue should be taken into account is that their administration route can be changed. ADMET tests should be performed before the development of these repurposing drugs in clinical trials. The choice of the route is a relevant aspect in serious infections in hospitalized patients such as ventilated-associated pneumonia who patients are intubated and other circumstances in which the oral route is not available.
