Novobiocin Enhances Polymyxin Activity by Stimulating Lipopolysaccharide Transport.
Michael D MandlerVadim BaidinJames LeeKaranbir S PahilTristan W OwensDaniel E KahnePublished in: Journal of the American Chemical Society (2018)
Gram-negative bacteria are challenging to kill with antibiotics due to their impenetrable outer membrane containing lipopolysaccharide (LPS). The polymyxins, including colistin, are the drugs of last resort for treating Gram-negative infections. These drugs bind LPS and disrupt the outer membrane; however, their toxicity limits their usefulness. Polymyxin has been shown to synergize with many antibiotics including novobiocin, which inhibits DNA gyrase, by facilitating transport of these antibiotics across the outer membrane. Recently, we have shown that novobiocin not only inhibits DNA gyrase but also binds and stimulates LptB, the ATPase that powers LPS transport. Here, we report the synthesis of novobiocin derivatives that separate these two activities. One analog retains LptB-stimulatory activity but is unable to inhibit DNA gyrase. This analog, which is not toxic on its own, nevertheless enhances the lethality of polymyxin by binding LptB and stimulating LPS transport. Therefore, LPS transport agonism contributes substantially to novobiocin-polymyxin synergy. We also report other novobiocin analogs that inhibit DNA gyrase better than or equal to novobiocin, but bind better to LptB and therefore have even greater LptB stimulatory activity. These compounds are more potent than novobiocin when used in combination with polymyxin. Novobiocin analogs optimized for both gyrase inhibition and LPS transport agonism may allow the use of lower doses of polymyxin, increasing its efficacy and safety.
Keyphrases
- gram negative
- inflammatory response
- multidrug resistant
- anti inflammatory
- circulating tumor
- cell free
- single molecule
- lps induced
- toll like receptor
- oxidative stress
- acinetobacter baumannii
- pseudomonas aeruginosa
- cystic fibrosis
- escherichia coli
- molecular docking
- immune response
- circulating tumor cells
- endoplasmic reticulum