Advancing the Discovery and Development of New Antibiotics through Drug Repurposing

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Novel Antimicrobial Agents".

Deadline for manuscript submissions: 31 March 2024 | Viewed by 1602

Special Issue Editor

Prof. Dr. Songping Huang
E-Mail Website
Guest Editor
Department of Chemistry and Biochemistry, Kent State University, Kent, OH 44240, USA
Interests: antibiotics; durg design; medicinal chemistry

Special Issue Information

Dear Colleagues,

Antimicrobial resistance (AMR) has now evolved in every class of antibiotics that have ever entered clinical use. The situation is worsened by the shrinking rate of return on the discovery of novel antibiotics. Current commercial antibiotics have two different origins: (1) natural products excreted by soil-dwelling Streptomyces, and (2) synthetic organic compounds. After eight decades of intensive screening and development, soil samples have failed to yield new classes of antibiotics since the end of the so-called golden era of antibiotic discovery. Although synthetic organic compounds have provided some important complementary classes of antibiotics, as represented by the advent of fluoroquinolones (e.g., ciprofloxacin), newer members from the family of synthetic antibiotics often share the known antimicrobial targets with the existing drugs in this class, making them susceptible to the development of the same type of resistance evolved in the previous members. In light of the high failure rates, considerable costs, and particularly substantial time spans of drug discovery and development, repurposing existing non-antibiotic drugs to treat multidrug-resistant bacterial infections should constitute an attractive approach to mitigating the threat of AMR. 

Prof. Dr. Songping Huang
Guest Editor

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Published Papers (2 papers)

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Research

15 pages, 6487 KiB  
Article
Repurposing Mitomycin C in Combination with Pentamidine or Gentamicin to Treat Infections with Multi-Drug-Resistant (MDR) Pseudomonas aeruginosa
Antibiotics 2024, 13(2), 177; https://doi.org/10.3390/antibiotics13020177 - 10 Feb 2024
Viewed by 568
Abstract
The aims of this study were (i) to determine if the combination of mitomycin C with pentamidine or existing antibiotics resulted in enhanced efficacy versus infections with MDR P. aeruginosa in vivo; and (ii) to determine if the doses of mitomycin C and [...] Read more.
The aims of this study were (i) to determine if the combination of mitomycin C with pentamidine or existing antibiotics resulted in enhanced efficacy versus infections with MDR P. aeruginosa in vivo; and (ii) to determine if the doses of mitomycin C and pentamidine in combination can be reduced to levels that are non-toxic in humans but still retain antibacterial activity. Resistant clinical isolates of P. aeruginosa, a mutant strain over-expressing the MexAB-OprM resistance nodulation division (RND) efflux pump and a strain with three RND pumps deleted, were used. MIC assays indicated that all strains were sensitive to mitomycin C, but deletion of three RND pumps resulted in hypersensitivity and over-expression of MexAB-OprM caused some resistance. These results imply that mitomycin C is a substrate of the RND efflux pumps. Mitomycin C monotherapy successfully treated infected Galleria mellonella larvae, albeit at doses too high for human administration. Checkerboard and time–kill assays showed that the combination of mitomycin C with pentamidine, or the antibiotic gentamicin, resulted in synergistic inhibition of most P. aeruginosa strains in vitro. In vivo, administration of a combination therapy of mitomycin C with pentamidine, or gentamicin, to G. mellonella larvae infected with P. aeruginosa resulted in enhanced efficacy compared with monotherapies for the majority of MDR clinical isolates. Notably, the therapeutic benefit conferred by the combination therapy occurred with doses of mitomycin C close to those used in human medicine. Thus, repurposing mitomycin C in combination therapies to target MDR P. aeruginosa infections merits further investigation. Full article
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17 pages, 3616 KiB  
Article
Unexpected Inhibitory Effect of Octenidine Dihydrochloride on Candida albicans Filamentation by Impairing Ergosterol Biosynthesis and Disrupting Cell Membrane Integrity
Antibiotics 2023, 12(12), 1675; https://doi.org/10.3390/antibiotics12121675 - 28 Nov 2023
Cited by 1 | Viewed by 840
Abstract
Candida albicans filamentation plays a significant role in developing both mucosal and invasive candidiasis, making it a crucial virulence factor. Consequently, exploring and identifying inhibitors that impede fungal hyphal formation presents an intriguing approach toward antifungal strategies. In line with this anti-filamentation strategy, [...] Read more.
Candida albicans filamentation plays a significant role in developing both mucosal and invasive candidiasis, making it a crucial virulence factor. Consequently, exploring and identifying inhibitors that impede fungal hyphal formation presents an intriguing approach toward antifungal strategies. In line with this anti-filamentation strategy, we conducted a comprehensive screening of a library of FDA-approved drugs to identify compounds that possess inhibitory properties against hyphal growth. The compound octenidine dihydrochloride (OCT) exhibits potent inhibition of hyphal growth in C. albicans across different hyphae-inducing media at concentrations below or equal to 3.125 μM. This remarkable inhibitory effect extends to biofilm formation and the disruption of mature biofilm. The mechanism underlying OCT’s inhibition of hyphal growth is likely attributed to its capacity to impede ergosterol biosynthesis and induce the generation of reactive oxygen species (ROS), compromising the integrity of the cell membrane. Furthermore, it has been observed that OCT demonstrates protective attributes against invasive candidiasis in Galleria mellonella larvae through its proficient eradication of C. albicans colonization in infected G. mellonella larvae by impeding hyphal formation. Although additional investigation is required to mitigate the toxicity of OCT in mammals, it possesses considerable promise as a potent filamentation inhibitor against invasive candidiasis. Full article
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