The emergence of new resistance mechanisms, the failure of classical antibiotics in clinic, the decrease in the development of antibiotics in the industry are all challenges that lead us to consider new strategies for the treatment of infectious diseases. Indeed, in recent years controversy has intensified over strains resistant to carbapenem and/or colistin. Various therapeutic solutions are used to overcome administration of last line antibiotics. In this context, drug repurposing, which consists of using a non-antibiotic compound to treat multi-drug resistant bacteria (MDR), is encouraged. In this review, we first report what may have led to drug repurposing. Main definitions, advantages and drawbacks are summarized. Three major methods are described: phenotypic, computational and serendipity. In a second time we will focus on the current knowledge in drug repurposing for carbapenem and colistin-resistant bacteria with different studies describing repurposed compounds tested on Gram-negative bacteria. Furthermore, we show that drug combination therapies can increase successful by drug repurposing strategy. In conclusion, we discuss the pharmaceutical industries that have little interest in reprofiling drugs due to lack of profits. We also consider what a clinician might think of the indications of these uncommon biologists to treat MDR bacterial infections and avoid therapeutic impasses.

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Immunodepression, whether due to HIV infection or organ transplantation, has increased human vulnerability to fungal infections. These conditions have created an optimal environment for the emergence of opportunistic infections, which is concomitant to the increase in antifungal resistance. The use of conventional antifungal drugs as azoles and polyenes can lead to clinical failure, particularly in immunocompromised individuals. Difficulties related to treating fungal infections combined with the time required to develop new drugs, require urgent consideration of other therapeutic alternatives. Drug repurposing is one of the most promising and rapid solutions that the scientific and medical community can turn to, with low costs and safety advantages. To treat life-threatening resistant fungal infections, drug repurposing has led to the consideration of well-known and potential molecules as a last-line therapy. The aim of this review is to provide a summary of current antifungal compounds and their main resistance mechanisms, following by an overview of the antifungal activity of non-traditional antimicrobial drugs. We provide their eventual mechanisms of action and the synergistic combinations that improve the activity of current antifungal treatments. Finally, we discuss drug repurposing for the main emerging multidrug resistant (MDR) fungus, including the Candida auris, Aspergillus or Cryptococcus species.

Candida auris is an emerging multidrug-resistant yeast causing nosocomial infections and associated with high mortality in immunocompromised patients. Rapid identification and characterisation are necessary for diagnosis and containing its spread. In this study, we present a selective culture medium for all C. auris clades. This medium is sensitive with a limit of detection ranging between 101 and 102 CFU/mL. The 100% specificity of SCA (specific C. auris) medium is confirmed on a set of 135 Candida strains, 50 bacterial species and 200 human stool samples. Thus, this medium specifically selects for C. auris isolation from clinical samples, allowing the latter to study its phenotypic profile.

Objectives The antiviral zidovudine has been recently identified as an active drug against resistant Enterobacteriaceae, but prevalence of resistance to this compound remains unknown. The aim was to estimate the prevalence of clinical Escherichia coli isolates resistant to zidovudine and to decipher the mechanism of zidovudine resistance. Methods We screened 537 isolates on zidovudine-containing agar plates and studied their thymidine kinase (tdk) gene sequences, the putative target involved in zidovudine resistance. Moreover, sequence analysis of 633 complete genomes of E. coli was performed to investigate mutation in the tdk gene. A comparative genomic analysis was done on an in vitro zidovudine-resistant mutant. Results After screening on our medium containing 2.7 mg/L (10 μM) zidovudine, nine strains had a zidovudine MIC >26.7 mg/L. The gene was absent in three isolates, inactivated by an IS (IS1X2 and ISApl1) in two isolates and mutated in four isolates. A genomic analysis of 633 E. coli genomes showed heterogeneity of the tdk gene sequence, with 27 different sequences. Among them, three genomes showed an inactivation of the gene (IS, stop codon and no tdk gene sequence). The in vitro mutant E. coli had 27 SNPs in eight genes of the core genome compared with the initial strain. Conclusions Our study reports zidovudine-resistant clinical isolates of E. coli, presumably related to tdk inactivation. Diversity of Tdk in bacterial genomes can be large. Other mechanisms need to be considered in zidovudine resistance. The use of zidovudine in antibiotic-resistant infections needs to be in combination and should be tested before clinical administration.

Alternative strategies against multidrug-resistant (MDR) bacterial infections are suggested to clinicians, such as drug repurposing, which uses rapidly available and marketed drugs. We gathered a collection of MDR bacteria from our hospital and performed a phenotypic high-throughput screening with a 1280 FDA-approved drug library. We used two Gram positive (Enterococcus faecium P5014 and Staphylococcus aureus P1943) and six Gram negative (Acinetobacter baumannii P1887, Klebsiella pneumoniae P9495, Pseudomonas aeruginosa P6540, Burkholderia multivorans P6539, Pandoraea nosoerga P8103, and Escherichia coli DSM105182 as the reference and control strain). The selected MDR strain panel carried resistance genes or displayed phenotypic resistance to last-line therapies such as carbapenems, vancomycin, or colistin. A total of 107 compounds from nine therapeutic classes inhibited >90% of the growth of the selected Gram negative and Gram positive bacteria at a drug concentration set at 10 µmol/L, and 7.5% were anticancer drugs. The common hit was the antiseptic chlorhexidine. The activity of niclosamide, carmofur, and auranofin was found against the selected methicillin-resistant S. aureus. Zidovudine was effective against colistin-resistant E. coli and carbapenem-resistant K. pneumoniae. Trifluridine, an antiviral, was effective against E. faecium. Deferoxamine mesylate inhibited the growth of XDR P. nosoerga. Drug repurposing by an in vitro screening of a drug library is a promising approach to identify effective drugs for specific bacteria.

Surveillance of antibiotic resistance has become a public global concern after the rapid worldwide dissemination of several antibiotic resistance genes. Here we report the role of the Institut Hospitalo-Universitaire Méditerranée Infection created in 2011 in the identification and description of multidrug-resistant bacteria thanks to collaborations and training of students from the Mediterranean basin and from African countries. Since the creation of the institute, 95 students and researchers have come from 19 different countries from these areas to characterize 6359 bacterial isolates from 7280 samples from humans (64%), animals (28%) and the environment (8%). Most bacterial isolates studied were Gram-negative bacteria (n = 5588; 87.9%), mostly from Algeria (n = 4190), Lebanon (n = 946), Greece (n = 610), Saudi Arabia (n = 299) and Senegal (n = 278). Antibiotic resistance was diversified with the detection and characterization of extended-spectrum β-lactamases, carbapenemases and resistance to colistin, vancomycin and methicillin. All those studies led to 97 indexed international scientific papers. Over the last 6 years, our institute has created a huge network of collaborations by training students that plays a major role in the surveillance of resistance to antibiotics in these countries.

Primary infection during pregnancy by the protozoan Toxoplasma gondii can be worrisome because transmission to the fetus may lead to congenital toxoplasmosis (CT). Neonatal diagnosis is usually performed by serological profile comparison of the mother and newborn. As previously reported in 2012 by C. L’Ollivier et al., three IgM bands at 75, 90 and 100 kDa called the “IgM triplet” has caught our attention and seems to be pathognomonic of CT. This retrospective multicenter study involved nine reference laboratories included in the French National Reference Center for Toxoplasmosis network and concerned determining the specificity and sensitivity of this IgM triplet. On this basis, we were able to propose a new read of the comparison of IgG and IgM immunoblot profiles of mother and infant to increase the sensitivity of this diagnostic marker. The effect of the trimester of pregnancy at the time of infection, but also of maternal treatment with pyrimethamine/sulfadiazine/folinic acid on the presence of this IgM triplet in the infant, could be studied. The presence of the triplet appears pathognomonic for the diagnosis of CT, and it increased the sensitivity of the immunoblot assay from 55.04% to 72.48%. As a result, it would be wise to enhance conventional immunoblot reading by adding the presence of the three IgM bands in the infant pattern for neonatal diagnosis of CT.