Carlson presented the findings during a talk Monday morning in the Division of Biochemistry and Chemical Biology.<\/p>\n
\u201cPolymyxins are cationic molecules. They interact with the negatively charged cell envelope of bacteria\u2014in particular a molecule called lipid A, which is phosphorylated,\u201d Carlson said in an interview before her presentation. Bacteria can respond to polymyxins and gain resistance by installing cationic groups onto lipid A, preventing electrostatic attraction, she said.<\/p>\n
Carlson has spent years working on two-component signaling systems in bacteria. One of the two components in the system is a histidine kinase, which detects environmental change and transfers a phosphate group to the second component, a response regulator. The response regulator then regulates the bacteria\u2019s gene expression to turn on its defenses.<\/p>\n
In theory, histidine kinase inhibitors (HKIs) could prevent bacteria from sensing antimicrobials and activating resistance mechanisms. So Carlson\u2019s lab screened over 53,000 molecules for HKIs and identified 2-aminobenzothiazoles as promising candidates.<\/p>\n
Some 2-aminobenzothiazoles \u201ccan even resensitize the bacteria by 16-32-fold,\u201d acting as an adjuvant and essentially moving polymyxin sensitivity back to wild-type levels, Carlson said. Her data show that this resensitization works because the molecules prevent the modification of lipid A.<\/p>\n
But her recent work indicates that the exact mechanism of action may be somewhat misunderstood, Carlson said. \u201cWe think that we\u2019d be inhibiting a protein called PhoQ,\u201d an important histidine kinase. \u201cWhen we generated that protein [PhoQ] in vitro, these molecules are extremely poor inhibitors, so there is some disconnect between what\u2019s actually happening in the cells and what\u2019s happening in vitro, and that\u2019s kind of where the project sits right now.\u201d<\/p>\n
Helen Blackwell<\/a>, a chemical biologist at the University of Wisconsin\u2013Madison who knows Carlson\u2019s work well but didn\u2019t participate in this research, said in an interview before Carlson\u2019s presentation that HKIs are a tricky target. \u201cNot a lot of people have gone after that. It\u2019s just a hard problem.\u201d<\/p>\n But the implications for pursuing histidine kinases in two-component systems could have big implications, Blackwell said. Such signaling systems \u201cplay really important roles in infection by a lot of really notorious pathogens,\u201d she added. \u201cThey\u2019re nonessential pathways. . . . If you knock down a two-component signaling system, typically you\u2019re not going to kill the bacteria. Therefore, resistance development is going to be limited.\u201d<\/p>\n Even though 2-aminobenzothiazoles don\u2019t seem to inhibit PhoQ in vitro, Carlson is excited to figure out exactly why the molecules might be such good adjuvants. \u201cI think one of the challenges of science is that you want your hypothesis to be true, and then you evaluate things and figure out, like, \u2018Nope, biology is tricking us,\u2019\u2009\u201d she said. \u201cSo now we\u2019re kind of going down a new road, and perhaps we\u2019ll find a novel way that these molecules are resensitizing the bacteria to polymyxins.\u201d<\/p>\n
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