Antibacterial Nucleoside Natural Products Inhibiting Phospho-MurNAc-Pentapeptide Translocase; Chemistry and Structure-Activity Relationship.

Abstract

The continued emergence of drug-resistance to existing antibacterial agents represents a severe and ongoing public health concern, which demands the discovery of new antibiotics. However the number of novel classes of antibacterial drugs launched in the clinic has been remarkably slow since the 1960s, and it is urgent to develop novel antibacterial agents to fight against drug-resistant bacterial pathogens. Peptidoglycan is a component of the bacterial cell wall, which consists of a repeated N-acetylmuramic acid (MurNAc) and Nacetylglucosamine (GluNAc) polymer cross-linked with polypeptides, and is a good target for antibacterial drug discovery. Among enzymes responsible for its biosynthesis, phospho-MurNAc-pentapeptide translocase (MraY) is a novel and promising target. Many nucleoside natural products, which strongly inhibit MraY, have been found in nature. This review will summarize the synthesis and biological properties of selected MraY inhibitory nucleoside natural products and their analogues synthesized in our laboratory and by others.

Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis

“…To date, several derivatives of uridylpeptide natural products have been generated through engineering of the organisms that produce the natural products or through semi-synthetic approaches and, as such, feature limited structural variation171819202122232425. A number of synthetic studies have also been reported on uridylpeptide natural products and analogues2627282930313233, some of which have been shown to possess antimicrobial activity78. The focus of the present study was to develop a rapid and divergent synthetic strategy to access a diverse library of sansanmycin analogues that would enable the determination of key structure-activity relationships specifically against Mtb.…”

“…4a)7. Whilst inhibition of MraY has been unequivocally determined for some members of the family82528363738, including a recently published structure of a complex of muraymycin D2 with the Aquifex aeolicus enzyme25, the antibacterial activity of other nucleoside antibiotics, including the sansanmycins, have only been predicted to be caused by inhibition of this enzyme. Furthermore, structural analogues of the nucleoside antibiotics have, on several occasions, been shown not to inhibit MraY, but to target other essential enzymes, suggesting that structural changes to the natural product can attenuate and even switch activity to other bacterial enzymes3940.…”

“…Approximately 65% of antibacterials approved for use between 1981 and 2010 were natural products or natural product derivatives56, including currently employed TB drugs for example, rifampicin and the aminoglycosides. The sansanmycins belong to the uridylpeptide natural product family, a sub-class of the structurally diverse nucleoside antibiotics78 that include the liposidomycins9, caprazamycins10, capuramycins1112 and muraymycins13. The sansanmycins are produced by the soil bacterium Streptomyces sp.…”

Muraymycin Nucleoside Antibiotics: Structure-Activity Relationship for Variations in the Nucleoside Unit

“…The resultant crude product was purified by semipreparative HPLC (method 1) to give 14 (bis-TFA salt) as a colorless foam (3.5 mg, 13% over 2 steps from 19). 1 Thymidine-derived muraymycin analogue (15): Nucleosyl amino acid ester 20 (25 mg, 53 µmol) was dissolved in THF (3 mL), and a solution of aldehyde 17 [42] (42 mg, 68 µmol) in THF (3 mL) was added. The reaction mixture was stirred over molecular sieve (3 Å) at rt for 24 h. NaBH(OAc) 3 (23 mg, 0.11 mmol) and Amberlyst 15 TM (3.5 mg, 11 µmol) were added and stirring was continued at rt for 24 h. The reaction mixture was filtered and the residue was washed with EtOAc (150 mL).…”

“…Nucleoside antibiotics are naturally produced secondary metabolites acting as MraY inhibitors. Several subclasses such as muraymycins, mureidomycins, tunicamycins, liposidomycins, and capuramycins have been reported [13][14][15][16]. Our research on nucleoside antibiotics mainly focusses on muraymycins which were isolated from Streptomyces sp.…”