The present work aims to examine the worrying problem of antibiotic resistance and the emergence of multidrug-resistant bacterial strains, which have now become really common in hospitals and risk hindering the global control of infectious diseases. After a careful examination of these phenomena and multiple mechanisms that make certain bacteria resistant to specific antibiotics that were originally effective in the treatment of infections caused by the same pathogens, possible strategies to stem antibiotic resistance are analyzed. This paper, therefore, focuses on the most promising new chemical compounds in the current pipeline active against multidrug-resistant organisms that are innovative compared to traditional antibiotics: Firstly, the main antibacterial agents in clinical development (Phase III) from 2017 to 2020 are listed (with special attention on the treatment of infections caused by the pathogens Neisseria gonorrhoeae, including multidrug-resistant isolates, and Clostridium difficile), and then the paper moves on to the new agents of pharmacological interest that have been approved during the same period. They include tetracycline derivatives (eravacycline), fourth generation fluoroquinolones (delafloxacin), new combinations between one β-lactam and one β-lactamase inhibitor (meropenem and vaborbactam), siderophore cephalosporins (cefiderocol), new aminoglycosides (plazomicin), and agents in development for treating drug-resistant TB (pretomanid). It concludes with the advantages that can result from the use of these compounds, also mentioning other approaches, still poorly developed, for combating antibiotic resistance: Nanoparticles delivery systems for antibiotics.

We selected the PnpI/PupG (PNP) with specificity for ribo- and deoxyriboguanosine and ribo- and deoxyriboinosine and the Up/Pdp (UP) with specificity for uridine, thymidine, and deoxyuridine from the purine and pyrimidine salvage pathway of the Gram-positive bacterium Bacillus subtilis. Then, an extensive study of the UP (uridine phosphorylase) and PNP (purine nucleoside phosphorylase) immobilization and stabilization was carried out: optimal UP preparation was achieved by immobilization onto Sepabeads coated with poly(ethyleneimine) and finally cross-linked with aldehyde dextran (UP-Sep-PEI-Dx); optimal immobilized PNP was prepared onto glyoxyl-agarose. Both derivatives were highly stable and active even under drastic experimental conditions (pH 10, 45 degrees C) unlike the free enzymes which were promptly inactivated. The derivatives prepared were successfully used in the synthesis of 2'-deoxyguanosine by enzymatic transglycosylation in aqueous solution between 2'-deoxyuridine and guanine.

This protocol describes the regioselective deprotection of single hydroxyls in peracetylated monosaccharides and disaccharides by enzymatic or chemoenzymatic strategies. The introduction of a one-pot enzymatic step by using immobilized biocatalysts obviates the requirement to carry out tedious workups and time-consuming purifications. By using this straightforward protocol, different per-O-acetylated glycopyranosides (mono- or disaccharides, 1-substituted or glycals) can be transformed into a whole set of differentially monodeprotected 1-alcohols, 3-alcohols, 4-alcohols and 6-alcohols in high yields. These tailor-made glycosyl acceptors can then be used for stereoselective glycosylation for oligosaccharide and glycoderivative synthesis. They have been successfully used as building blocks to synthesize tailor-made di- and trisaccharides involved in the structure of lacto-N-neo-tetraose and precursors of the tumor-associated carbohydrate antigen T and the antitumoral drug peracetylated β-naphtyl-lactosamine. We are able to prepare a purified monoprotected carbohydrate in between 1 and 4 d. With this protocol, the small library of monodeprotected products can be synthesized in 1-2 weeks.

The comparison between the biocatalyzed synthesis of araA here described and the chemical synthesis of this nucleoside showed that the enzymatic route is superior (less steps, milder conditions and reagents, easier downstream, lower E-factor).