The race between drug introduction and appearance of microbial resistance. Current balance and alternative approaches

Repurposed anti-cancer drugs: the future for anti-infective therapy?

“…Differences in these parameters between the human and bacterial enzymes may influence the efficacy of the repurposing attempt. Moreover, some of the approved anticancer compounds target processes absent in prokaryotic cells, but still show antibacterial activity, for example, inhibitors of signal transduction like sorafenib, gefitinib, ibrutinib or imatinib or modulators of hormone effects like raloxifene, toremifene, or tamoxifen [2]. These drugs may directly bind bacterial proteins or act through a hostmediated response [2].…”

“…Moreover, some of the approved anticancer compounds target processes absent in prokaryotic cells, but still show antibacterial activity, for example, inhibitors of signal transduction like sorafenib, gefitinib, ibrutinib or imatinib or modulators of hormone effects like raloxifene, toremifene, or tamoxifen [2]. These drugs may directly bind bacterial proteins or act through a hostmediated response [2]. Thus, drug repurposing will certainly benefit from pre-clinical research to characterize the mechanisms of action in bacteria.…”

“…To our knowledge no drug currently used in the clinic has been approved as anti-virulence as its primary use. However, several candidates for drug repurposing have been reported [2]. Among the most promising are the above mentioned anticancer drugs mitomycin C, which inhibits biofilm formation in E. coli, S. aureus, and P. aeruginosa, and 5-FU, which inhibits biofilm formation in E. coli, P. aeruginosa, and S. epidermidis, and represses QS and virulence in P. aeruginosa [2].…”

“…Among the most promising are the above mentioned anticancer drugs mitomycin C, which inhibits biofilm formation in E. coli, S. aureus, and P. aeruginosa, and 5-FU, which inhibits biofilm formation in E. coli, P. aeruginosa, and S. epidermidis, and represses QS and virulence in P. aeruginosa [2]. Other anti-cancer drugs that efficiently prevented biofilm formation are azacitidine (in S. pneumoniae), toremifene (in S. aureus), aminolevulinic acid (in S. aureus and S. epidermidis), while raloxifene inhibited pyocyanin production in P. aeruginosa, besides, it showed virulence reduction in an in vivo model of Caenorhabditis elegans [2]. The urgent need of new approaches to deal with the rise of antimicrobial resistance demands that industry and academia combine efforts to fully explore the potential of anti-virulence therapy and drug repurposing synergy.…”

“…Among infectious bacteria, there is a notable group that often are MDR and even pan-drug resistant and that are responsible for nosocomial infections, this group is known as ESKAPE for the species that constitute it: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species. Current efforts to develop improvements in combating these organisms include the modification of present antibiotics in order to increase their activity and to avoid resistance mechanisms, the discovery or development of new ones, as well as the utilization of alternative approaches such as co-administration of adjuvants that attack antibiotic resistance mechanisms, anti-microbial peptides, biological agents such as bacteriophages and targeting virulence instead of growth [2]. However, bringing a new drug to the clinic takes decades, and hence a way to accelerate the implementation of efficient antimicrobials is drug repurposing.…”