Deoxynybomycins inhibit mutant DNA gyrase and rescue mice infected with fluoroquinolone-resistant bacteria

Abstract

Fluoroquinolones are one of the most commonly prescribed classes of antibiotics, but fluoroquinolone resistance (FQR) is widespread and increasing. Deoxynybomycin (DNM) is a natural-product antibiotic with an unusual mechanism of action, inhibiting the mutant DNA gyrase that confers FQR. Unfortunately, isolation of DNM is difficult and DNM is insoluble in aqueous solutions, making it a poor candidate for development. Here we describe a facile chemical route to produce DNM and its derivatives. These compounds possess excellent activity against FQR methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci clinical isolates and inhibit mutant DNA gyrase in-vitro. Bacteria that develop resistance to DNM are re-sensitized to fluoroquinolones, suggesting that resistance that emerges to DNM would be treatable. Using a DNM derivative, the first in-vivo efficacy of the nybomycin class is demonstrated in a mouse infection model. Overall, the data presented suggest the promise of DNM derivatives for the treatment of FQR infections.

Predictive compound accumulation rules yield a broad-spectrum antibiotic

“…Thus, a rotatable bond and globularity analysis of antibacterial agents with Gram-positive-only activity was conducted and used to select the natural product deoxynybomycin (DNM) as a good candidate for conversion to a broad-spectrum agent. DNM has antibacterial activity through inhibition of wild-type and mutant DNA gyrase, and DNM and its derivatives are only active against Gram-positive bacteria 31,32 . DNM has no rotatable bonds and a globularity of 0.02, suggesting that the addition of an amine to a position that does not alter the DNM antibacterial activity would provide a derivative able to accumulate in and be active against Gram-negative pathogens.…”

Targeting Bacterial Topoisomerases: How to Counter Mechanisms of Resistance

“…A DNM derivative was able to rescue mice infected with fluoroquinoloneresistant MRSA [48]. The fluoroquinolone-resistant S. aureus strains selected for resistance to DNM treatment were resensitized to fluoroquinolones because such DNM-resistant strains reverted back to wild-type GyrA Ser84 [48]. Coresistance to fluoroquinolone and DNM could not be generated in the reported study, as no resistant colony was observed on treatment with both ciprofloxacin and DNM [48].…”

“…A related compound, deoxynybomycin (DNM, compound 4) and its derivatives, were synthesized and found to inhibit the activity of mutant Staphylococcus aureus gyrase with the fluoroquinolone-resistant substitutions at the conserved Ser84 [48]. A DNM derivative was able to rescue mice infected with fluoroquinoloneresistant MRSA [48].…”

“…A related compound, deoxynybomycin (DNM, compound 4) and its derivatives, were synthesized and found to inhibit the activity of mutant Staphylococcus aureus gyrase with the fluoroquinolone-resistant substitutions at the conserved Ser84 [48]. A DNM derivative was able to rescue mice infected with fluoroquinoloneresistant MRSA [48]. The fluoroquinolone-resistant S. aureus strains selected for resistance to DNM treatment were resensitized to fluoroquinolones because such DNM-resistant strains reverted back to wild-type GyrA Ser84 [48].…”

“…The fluoroquinolone-resistant S. aureus strains selected for resistance to DNM treatment were resensitized to fluoroquinolones because such DNM-resistant strains reverted back to wild-type GyrA Ser84 [48]. Coresistance to fluoroquinolone and DNM could not be generated in the reported study, as no resistant colony was observed on treatment with both ciprofloxacin and DNM [48]. It should be noted that the Ser that is conserved in most bacterial species is replaced by an Ala in M. tuberculosis gyrase [49,50], and nybomycin was observed to have antidormant mycobacterial activity [51].…”