GRP78/BiP/HSPA5/Dna K is a universal therapeutic target for human disease.
Bottom Line: The GRP78 inhibitor OSU-03012 (AR-12) interacted with sildenafil (Viagra) or tadalafil (Cialis) to rapidly reduce GRP78 levels in eukaryotes and as a single agent reduce Dna K levels in prokaryotes.Pre-treatment with OSU-03012/sildenafil reduced expression of the coxsakie and adenovirus receptor in parallel with it also reducing the ability of a serotype 5 adenovirus or coxsakie virus B4 to infect and to reproduce.OSU-03012 as a single agent at clinically relevant concentrations killed laboratory generated antibiotic resistant E. coli and clinical isolate multi-drug resistant N. gonorrhoeae and MRSE which was in bacteria associated with reduced Dna K and Rec A expression.
Affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298.Show MeSH
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Mentions: Similar data to that obtained in E. coli with OSU-03012 were also found Neisseria gonorrhoeae strains FA19, FA1090, MS11 and 1291 (Fig. 8A, data not shown). OSU-03012 treatment did not appear to alter the morphology of these coccoid bacteria, though as before, we noted that OSU-03012 reduced expression of Dna K and Rec A (Fig. 8B). In FA19, OSU-03012 and PDE5 inhibitors could interact to cause a greater than additive amount of bacteria killing (Fig. 8C). Data in prior panels had shown that unlike the growth inhibitory antibiotic chloramphenicol, OSU-03012 exhibited true bacteriocidal effects on cells that had yet to enter log-phase growth. Finally, using F89 and HO41 drug resistant N. gonorrhoeae isolates we determined whether OSU-03012 exhibited any antibiotic effect and whether it could enhance/restore the bacteriocidal properties of approved standard of care antibiotics. Treatment of F89 and HO41 bacteria with OSU-03012 caused a dose-dependent reduction in bacterial growth (Fig. 9A). Treatment of F89 and HO41 bacteria with OSU-03012 variably enhanced the lethality of Ceftriaxone, Ciprofloxin, or Azithromycin over a 5 h time course (Figures 9B and 9 C). Methicillin-resistant Staphylococcus epidermidis (MRSE) bacteria were noted to be at least as sensitive to OSU-03012 as were N. gonorrhoeae (F89, HO41), possibly moreso i.e. 2 μM OSU-03012 was not growth inhibitory in F89 and HO41 but reduced MRSA growth by ∼50%, and co-exposure of bacteria to OSU-03012 and sildenafil modestly enhanced the cyto-toxic effect beyond that of OSU-03012 alone (Fig. 9D).
Affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298.