**3.1 DNA, RNA and proteins inhibitors**

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

#### **Figure 1.** *Mechanisms of action of repurposed drugs against Gram-negative critical-priority pathogens.*


**101**

**Bacterial target**

Cell membrane

**Repurposed drug**

Niclosamide Oxyclozanide

Rafoxanide

Ivermectin

Mitotane Pentamidine

Robenidine

Ebselen

Bipolar disorder

and ischemic

stroke

Iron metabolism

Gallium Nitrate

Ebselen

Lymphoma and

Interferance with iron-dependent metabolic pathways in GNB

linhibition of TonB involved in iron acquisition by *A. baumannii* and *E. coli*

Reduction in the migration of immune cells from bone marrow to blood through the

reduction of MCP-1 and IL-18 in presence of *A. baumannii, P. aeruginosa* and *E. coli*

Enhancement of the killing activity of monocytes and macrophages towards *P. aeruginosa.*

Enhancement of the macrophage function towards *P. aeruginosa* via inhibiting the release of

nuclear protein high mobility group box-1

Reduction of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) release

[37]

[38, 39]

[51]

[36]

[31–33]

bladder cancer

Bipolar disorder

and ischemic

stroke

Host immune system

Tamoxifen

Calcitriol

GTS-21

**Table 1.**

*Repurposing drugs and their mechanisms of action.*

Inflammation

Breast cancer

Protozoal infection

Protozoal infection

Cancer

Helminthiasis

Helminthiasis

Helminthiasis Helminthiasis

**Clinical indications**

**Mechanism of action**

Increase of the negative surface charge of *A. baumannii* and *K. pneumoniae*

Reduction of the membrane potential and increase of aminoglucosides accumulation in *P. aeruginosa.* Increase of the membrane permeability of *A. baumannii*, *P. aeruginosa* and *K. pneumoniae*

Increase of the negative surface charge of *A. baumannii* and *K. pneumoniae*

Increase of the membrane permeability of *A. baumannii, P. aeruginosa* and *K. pneumoniae*

Increase of the membrane permeability of *A. baumannii, P. aeruginosa* and *K. pneumoniae*

Permeabilization of the outer membrane of *A. baumannii*, *P. aeruginosa* and *K. pneumoniae*

Alteration of the outer membrane of GNB, due to the interaction with membrane lipopolysaccharides

Alteration of the cell membrane of GNB

Inhibition of the TonB-mediated physiology of *A. baumannii* and *E. coli*

[51]

[47]

[49] [29] [50]

[48]

[30] [28, 46]

**Reference**

*Drugs Repurposing for Multi-Drug Resistant Bacterial Infections*

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

#### *Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications*


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

**Table 1.** *Repurposing drugs and their mechanisms of action.* as the superficial vesical carcinoma [40], has shown activity against *A. baumannii*, *P. aeruginosa* and *E. coli in vitro* and *in vivo* [16–18]. Mitomycin C binds to DNA during DNA synthesis and causes inhibition of its synthesis and function in *P. aeruginosa* and *E. coli* [18]. Cisplatin, approved for treatment of a number of cancers, was found to inhibit microbial cells growth [17, 20]. The mechanism of action of this drug has been attributed to the upregulation of the recA gene in *P. aeruginosa*, which is important for DNA repair, implicating that cisplatin could interfere with DNA replication [20]. Moreover, celecoxib, a non-steroidal anti-inflammatory drug (NSAID), has been tested in a *Caenorhabditis elegans* and in whole-animal *A. baumannii* and *P. aeruginosa* infection models. It was suggested that inhibit dosedependently the DNA, RNA and protein synthesis as in *Staphylococcus aureus* [19].

#### **3.2 Quorum sensing regulators**

QS inhibition and regulation have been reported as antibacterial properties of anticancer, anthelminthic, anti-inflammatory and hypoglycemic drugs such as 5-fluorouracil, raloxifene, niclosamide, meloxicam and metformin. 5-fluorouracil is a potent drug indicated for the treatment of different types of solid tumors, that has shown antibacterial activity *in vitro* [17, 22, 23]. The antibacterial mechanism of this drug has been proposed as QS inhibitor [23, 41]. Also, 5-fluorouracil has dual inhibition mechanisms including functioning as an alternative substrate resulting in miscoding DNA and RNA, and inhibiting thymidylate synthase [22]. Moreover, the selective estrogen receptor modulator (SERM) raloxifene, used in the prevention of osteoporosis and invasive breast cancer in post-menopausal women, has presented activity against Gram-negative bacilli (GNB). Raloxifene binds to PhzB2 which is involved in the production of pyocyanin, a pigment related with both the virulence factor and the QS signaling molecule in *P. aeruginosa* [24]. Regarding the anthelmintic drugs, niclosamide, used for the treatment of helminthiasis, has been reported to inhibit QS in *P. aeruginosa* in *Galleria mellonella* model by hindering the cell's response and production of the QS signaling molecules as N-3-oxododecanoylhomeserine lactone and N-butanoyl-homoserine lactone [15, 25]. Finally, meloxicam, a NSAID used to manage moderate-to-severe pain, and metformin, one of the most commonly prescribed oral hypoglycemic for treatment of type 2 diabetes, have been reported to interact with active sites and to inhibit the QS of *P. aeruginosa*, respectively [21, 26, 27]. Molecular docking study has shown that metformin could bind to LasR by hydrogen bonding and electrostatic interaction and to rhlR by hydrogen bonding only [21].

#### **3.3 Biofilm formation inhibitors and disruptors**

Compared with QS, much less drugs have been act on the biofilm formation. 5-fluorouracil has been revealed to regulate different genes involved in the biofilm formation by *P. aeruginosa* [41]. More specifically, meloxicam has been reported to inhibit biofilm formation of *P. aeruginosa* by decreasing the extracellular Psl, Pel and alginate production, three vital biofilm exopolysaccharides in this pathogen [26, 27]. Moreover, glatiramer acetate, a drug used in the treatment of multiple sclerosis, has also been shown to disrupt biofilm formation by GNB [42]. Finally, azathioprine, an immunosuppressive drug used for the treatment of Crohn's disease and other autoimmune diseases, has exhibited anti-biofilm activity against *P. aeruginosa* and *E. coli* through the inhibition of WspR [43]. WspR is a diguanylate cyclase involved in the regulation of a signal molecule called cyclic-di-GMP (c-di-GMP) known as a regulator of the bacterial biofilm formation [43]. The same mechanism of action has been used by ebselen to exhibit anti-biofilm activity

**103**

*Drugs Repurposing for Multi-Drug Resistant Bacterial Infections*

disorder, hearing loss and tinnitus and ischemic stroke.

which is involved in iron acquisition from host sources [51].

**3.5 Interaction with iron metabolism**

*A. baumannii* and *E. coli* [51].

**3.6 Host immune system modulators**

against *P. aeruginosa* [44, 45]. Ebselen, despite the fact that it is not an FDAapproved drug, it is being investigated in clinical trials for the treatment of bipolar

Various anthelmintic, anticancer and antiprotozoal drugs such as niclosamide, oxyclozanide, rafoxanide, ivermectin, mitotane, pentamidine and robenidine have been reported to interact with the bacterial cell membrane. Three anthelmintic drugs in combination with colistin have shown activity against GNB by the regulation of electric charges. Niclosamide and rafoxanide were discovered to increase the negative surface charge of bacterial membrane in *A. baumannii* and *K. pneumoniae* clinical strains *in vitro* [30, 47]. In turn, oxyclozanide has enhanced the activity of additional tobramycin against *P. aeruginosa* by reducing the membrane potential and increasing tobramycin accumulation [28]. This increase in the negative surface charges allow to restore the activity of colistin in colistin-resistant (Col-R) *A. baumannii* and *K. pneumoniae*, and the activity tobramycin in tobramycin-resistant *P. aeruginosa* [30, 47]. Not only the regulation of electric charges has been reported as mechanism of action of anthelmintic drugs, but the increase of bacterial membrane permeabilization has also been reported. Oxyclozanide, rafoxanide and ivermectin have been shown to increase the membrane permeability of *A. baumannii*, *P. aeruginosa* and *K. pneumoniae*, especially in Col-R strains [46–48]. Moreover, Tran et al. have demonstrated that mitotane, a FDA-approved antineoplastic drug, in combination of polymyxin B lead mitotane to enter inside *A. baumannii*, *P. aeruginosa* and *K. pneumoniae* through the permeabilization of the outer membrane by polymyxin B [49]. Additionally, antiprotozoal drugs, pentamidine and robenidine, possess a mechanism of action that disturbs the outer membrane of GNB, due to the interaction with membrane lipopolysaccharides (LPS) [29, 50]. Finally, ebselen has also presented antibacterial effect against *A. baumannii* and *E. coli* by inhibiting the TonB-mediated physiology,

Antunes et al. have demonstrated that virulent bacteria are able to acquire iron in the blood and tissues [33]. Given the essential role of iron in bacterial physiology and pathogenicity, iron uptake and metabolism have become attractive targets for the development of new antibacterial agents [52, 53]. The ion gallium [Ga(III)], a ferric iron [Fe(III)] mimetic, has been shown to inhibit the growth of many bacterial species by interfering with iron-dependent metabolic pathways. Therefore, gallium drugs have gained special interest in the fight of MDR-GNB infections [31]. Gallium nitrate is an anticancer drug that was approved by the FDA for the treatment of cancer-associated hypercalcemia. Antibacterial properties of gallium nitrate have been previously reported against GNB infections, both *in vitro* and *in vivo* [31–35]. In addition, Ebselen as mentioned before has the characteristic to inhibit TonB in

Also, some drugs that modulate host immune system have reported antibacterial activity against GNB. Tamoxifen, a SERM used for breast cancer treatment, can reduced the migration of immune cells from bone marrow to blood through the reduction of monocytes chemoattractant protein 1 (MCP-1) and IL-18 in a murine model of sepsis by *A. baumannii*, *P. aeruginosa* and *E. coli* [36]. Moreover, tamoxifen

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

**3.4 Interaction with cell membrane**

against *P. aeruginosa* [44, 45]. Ebselen, despite the fact that it is not an FDAapproved drug, it is being investigated in clinical trials for the treatment of bipolar disorder, hearing loss and tinnitus and ischemic stroke.
