Combating Multidrug-Resistant Pathogens with Host-Directed Nonantibiotic Therapeutics

Abstract

Earlier, we reported that three Food and Drug Administration-approved drugs, trifluoperazine (TFP; an antipsychotic), amoxapine (AXPN; an antidepressant), and doxapram (DXP; a breathing stimulant), identified from an murine macrophage cytotoxicity screen, provided mice with 40 to 60% protection against pneumonic plague when administered at the time of infection for 1 to 3 days. In the present study, the therapeutic potential of these drugs against pneumonic plague in mice was further evaluated when they were administered at up to 48 h postinfection. While the efficacy of TFP was somewhat diminished as treatment was delayed to 24 h, the protection of mice with AXPN and DXP increased as treatment was progressively delayed to 24 h. At 48 h postinfection, these drugs provided the animals with significant protection (up to 100%) against challenge with the agent of pneumonic or bubonic plague when they were administered in combination with levofloxacin. Likewise, when they were used in combination with vancomycin, all three drugs provided mice with 80 to 100% protection from fatal oral infection when they were administered at 24 h postinfection. Furthermore, AXPN provided 40 to 60% protection against respiratory infection with when it was administered at the time of infection or at 24 h postinfection. Using the same cytotoxicity assay, we identified an additional 76/780 nonantibiotic drugs effective against For, 121 nonantibiotic drugs were identified to inhibit bacterium-induced cytotoxicity in murine macrophages. Of these 121 drugs, 13 inhibited the macrophage cytotoxicity induced by two additional multiple-antibiotic-resistant strains. Six of these drugs decreased the intracellular survival of all three strains in macrophages. These results provided further evidence of the broad applicability and utilization of drug repurposing screening to identify new therapeutics to combat multidrug-resistant pathogens of public health concern.

New Host-Directed Therapeutics for the Treatment of Clostridioides difficile Infection

“…Indeed, our previous report showed that when combined with a subclinical dose of vancomycin, AXPN, DXP, and TFP elicited enhanced protection of mice against CDI, with 80 to 100% survival rates reported when treatment ensued 24 h postinfection. (23). Hence, our data demonstrate the potential utility of repurposing AXP, DXP, and TFP to combat CDI in high-risk patients and provide further evidence of the crucial involvement of the innate immune response in influencing disease outcome.…”

“…Lead drugs protect mice from lethal C. difficile infection. We recently demonstrated in a mouse model of lethal CDI that a combination of a subclinical dose of vancomycin with lead drugs AXPN, DXP, and TFP, administered as adjunct therapy (24 h postinfection), reduced lethality by 80 to 100% (23). While TFP alone provided 60% protection (22), we did not determine the therapeutic efficacy of AXPN and DXP alone.…”

Drugs Repurposing for Multi-Drug Resistant Bacterial Infections

“…Other drugs with different modes of action and clinical indications have been evaluated as antibacterial agents in monotherapy and in combined therapy with a large list of antibiotics against E. coli and K. pneumoniae in vitro and in animal models. Amoxapine has been reported to present therapeutic efficacy in an experimental murine model of respiratory infection by K. pneumoniae [93]. In addition, pentamidine in combination with different antibiotics ([novobiocin, erythromycin and rifampin] and [amikacin, tobramycin, tigecycline and rifampin]) has presented synergistic activity in vitro against different clinical isolates of E. coli harboring mcr-1 and K. pneumoniae producing carbapenemases, respectively [94].…”

Repurposing approved drugs on the pathway to novel therapies

“…For example, drugs approved for different indications, chosen from a 400 compound library, inhibited the ability of several pathogenic bacteria to grow in macrophages. Trifluoperazine (antipsychotic), amoxapine (antidepressant), and doxapram (a breathing stimulant) protected up to 60% of animals tested against plague ( Yersinia pestis ), whereby full protection required coadministration of vancomycin . The same group found that, at 33 µM, 9% to 13% of 780 tested drugs inhibited the growth of Klebsiella pneumoniae or Acinetobacter baumannii in macrophages.…”