Nucleoside Derived Antibiotics to Fight Microbial Drug Resistance: New Utilities for an Established Class of Drugs?

Abstract

Novel antibiotics are urgently needed to combat the rise of infections due to drug-resistant microorganisms. Numerous natural nucleosides and their synthetically modified analogues have been reported to have moderate to good antibiotic activity against different bacterial and fungal strains. Nucleoside-based compounds target several crucial processes of bacterial and fungal cells such as nucleoside metabolism and cell wall, nucleic acid, and protein biosynthesis. Nucleoside analogues have also been shown to target many other bacterial and fungal cellular processes although these are not well characterized and may therefore represent opportunities to discover new drugs with unique mechanisms of action. In this Perspective, we demonstrate that nucleoside analogues, cornerstones of anticancer and antiviral treatments, also have great potential to be repurposed as antibiotics so that an old drug can learn new tricks.

Immucillins in Infectious Diseases

“…17–19 Many natural product nucleoside antibiotics have been discovered by cell inhibitor screening or, more recently, by genomic interpretation and can inhibit cell wall biosynthesis, protein translation, or enzymes of nucleic acid synthesis. 20,21 The Immucillins differ from the usual ribosyl or base modifications of nucleoside antibotics, as they are produced by directed chemical synthesis to be transition state analogues against specific targets. 22,23 The inhibition potential of transition state analogues is enhanced by the picomolar affinity commonly attained with transition state analogues, as demonstrated by the examples of inducing purine starvation in P. falciparum and inhibition of the menaquinone pathway in H. pylori .…”

Symmetrical Diamidates as a Class of Phosphate Prodrugs to Deliver the 5′‐Monophosphate Forms of Anticancer Nucleoside Analogues

“…Current chemotherapeutic treatment of cancer and viral infections is largely based on the use of anti‐metabolites, in particular modified nucleoside analogues (NAs) that mimic natural purine or pyrimidine nucleosides . There is also strong evidence that NAs have potential as antibacterial agents . These molecules are often taken up by nucleoside transporters and then phosphorylated by specific nucleoside/nucleotide kinases to the corresponding 5′‐mono‐, di‐ and triphosphate forms.…”

“…[1] Therei sa lso strong evidence that NAs have potential as antibacterial agents. [2,3] These molecules are often taken up by nucleoside transporters and then phosphorylated by specific nucleoside/nucleotide kinases to the corresponding5 '-mono-, di-and triphosphate forms. These metabolites interfere with de novo synthesis of DNA/ RNA precursors, leading to inhibition of DNA/RNA synthesis, with subsequent suppression of tumour cell growth or virus replication.…”

“…MHz), 31 P( 202 MHz) and19 FNMR (470 MHz) spectra were recorded on aB ruker Avance5 00 MHz spectrometer at 25 8C. Chemical shifts (d)a re reported in parts per million (ppm) relative to internal CD3 OD ( 1 H: d = 3.34 ppm; 13 C: d = 49.86 ppm) and CDCl 3 ( 1 H: d = 7.26 ppm; 13 C: d = 77.36 ppm) or external 85 %H 3 PO 4 ( 31 P: d = 0.00 ppm). Coupling constants (J)a re expressed in Hertz.…”

Expedient synthesis and biological evaluation of alkenyl acyclic nucleoside phosphonate prodrugs

“…16,17 Discovered almost 30 years ago, a great wealth of research has been dedicated to the development of efficient synthetic methodologies that resulted in a great variety of ANPs. [18][19][20][21][22] These new structures offer a potential for the discovery of more effective drugs against a variety of infectious diseases including antiparasitic, [23][24][25][26][27][28][29] antimicrobial, [30][31][32][33] and antitubercolous 34,35 medicines. Among these synthetic strategies, quite recently, Agrofoglio's group has elaborated a novel, efficient and straightforward synthesis of C5-alkenyl substituted ANPs via olefin cross-metathesis.…”