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Since the discovery of penicillin, the forerunner of the most widely used class of antibiotics ( i.e. β-lactams), natural compounds and their derivatives represented a major source of antibacterial therapeutic products whose availability enabled modern medical practices (invasive surgery, organ transplant, etc .). However, the relentless emergence of resistant bacteria is challenging the long-term efficacy of antibiotics, also decreasing their economic attractiveness for big pharma, leading to a significant decay in antibacterial development in the 21 st century and an increased use of last-resort drugs such as carbapenems or colistin. Indeed, bacteria evolved an arsenal of resistance mechanisms, leading to the emergence of totally-drug resistant isolates, already sporadically isolated among Gram-negative bacterial species. To face this deadly peril, it is fundamental to explore new ground-breaking approaches. In view of the significance of both β-lactam antibiotics and the production of one or more β-lactamases as the major resistance mechanism (especially in Gram-negative bacteria), we implemented an original approach to selectively deliver antibacterial zidovudine (AZT) exploiting the β-lactamase-mediated hydrolysis of a β-lactam-conjugate prodrug. The synthesis of the targeted pronucleosides was performed in 5-7 steps and based on an original Pd-catalyzed cross-coupling reaction. Enzymatic and microbiological evaluations were performed to evaluate the synthesized pronucleosides, yielding new insights into molecular recognition of β-lactamase enzymes. This approach would potentially allow a targeted and selective eradication of antibiotic-resistant β-lactamase-producing (opportunistic) pathogens, as the inactive prodrug is unable to harm the commensal microbial flora.

Respiratory tract infections involving a variety of microorganisms such as viruses, bacteria, and fungi are a prominent cause of morbidity and mortality globally, exacerbating various pre-existing respiratory and non-respiratory conditions. Moreover, the ability of bacteria and viruses to coexist might impact the development and severity of lung infections, promoting bacterial colonization and subsequent disease exacerbation. Secondary bacterial infections following viral infections represent a complex challenge to be overcome from a therapeutic point of view. We report herein our efforts in the development of new bithiazole derivatives showing broad-spectrum antimicrobial activity against both viruses and bacteria. A series of 4-trifluoromethyl bithiazole analogues was synthesized and screened against selected viruses (hRVA16, EVD68, and ZIKV) and a panel of Gram-positive and Gram-negative bacteria. Among them, two promising broad-spectrum antimicrobial compounds (8a and 8j) have been identified: both compounds showed low micromolar activity against all tested viruses, 8a showed synergistic activity against E. coli and A. baumannii in the presence of a subinhibitory concentration of colistin, while 8j showed a broader spectrum of activity against Gram-positive and Gram-negative bacteria. Activity against antibiotic-resistant clinical isolates is also reported. Given the ever-increasing need to adequately address viral and bacterial infections or co-infections, this study paves the way for the development of new agents with broad antimicrobial properties and synergistic activity with common antivirals and antibacterials., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)