The lipopolysaccharide (LPS) containing outer membrane of Gram-negative bacteria prevent penetration of antibiotics, making them ineffective against infections. Polymyxins, including colistin, bind LPS and disrupt the outer membrane and hence are the drugs of last resort for treating Gram-negative infections; however, their toxicity limits their usefulness. These drugs function synergistically with many antibiotics, including novobiocin – a DNA gyrase inhibitor, by facilitating the transport of many across the outer membrane. Novobiocin was recently shown to stimulate LptB, the ATPase that powers LPS transport. Prof. Kahne's team synthesized derivatives of novobiocin by making structural changes to the noviose sugar and replacing the benzamide with a suitable group, hence separating the DNA gyrase inhibition and LptB stimulation activities from each other One set of these analogs is unable to inhibit DNA gyrase, making it nontoxic, while retaining LptB-stimulatory activity. These analogs improve the novobiocin−polymyxin synergy and enhance the lethality of polymyxin by binding LptB stimulation. Another set inhibit DNA gyrase better than or equal to novobiocin, but bind better to LptB and therefore have even greater LptB stimulatory activity. When used in combination with polymyxin, these analogs are more potent than novobiocin, and may allow the use of lower doses of polymyxin, increasing its efficacy and safety.