DRUG DISCOVERY SYNTHETIC BIOLOGY
Engineered bacteria detect gut inflammation in mice A new strain of engineered bacteria can detect inflammation in the colon of mice even after more than 1,000 bacterial divisions, researchers report (Nat. Biotechnol. 2017, DOI: 10.1038/nbt.3879). Such a microbe could help doctors diagnose and monitor diseases such as inflammatory bowel disease. Pamela A. Silver and coworkers at Harvard University engineered nonpathogenic Escherichia coli to detect and respond to tetrathionate, a transient product of a reactive oxygen species released by intestinal cells during inflammation. The researchers inserted two genetic circuits into the bacterial genome. The first circuit produces the transcriptional factor Cro in response to tetrathionate, and Cro triggers a second “memory” circuit to produce the protein β-galactosidase. Even when tetrathionate is no longer around, the bacteria “remember” the exposure and continue to produce both proteins. The researchers monitored inflammation in mice treated with the microbes by measuring β-galactosidase in the animals’ feces. The bacteria produced β-galactosidase in mice with intestinal infections and those genetically engineered to have high levels of inflammation. The researchers were even able to detect signs of inflammation in mice that had no visible signs of it, which suggests that the bacteria can detect low-level, subclinical inflammation. Because the bacteria didn’t acquire mutations that shut down the engineered circuits, they could maintain their responsiveness to tetrathionate for at least six months, which equals approximately 1,600 generations of engineered bacteria.—CELIA
ARNAUD
Vancomycin triple threat antibiotic Modified drug uses three mechanisms of action to treat drug-resistant bacterial infections Researchers have created a modified form quaternary trimethylammonium group, of the approved antibacterial drug vancomakes the bacterial cell membrane more mycin (Vancocin) that has three indepenpermeable, compromising microbes’ ability dent mechanisms of action, boosting its to control their internal environment. potency and minimizing the potential for The three revisions increase potency, bacteria to develop resistance to it. meaning that doctors could use less of the Vancomycin, a bacterial natural product, modified agent per dose. But the methhad long been an antibiotic of last resort ylene substitution is difficult, so making because it remained effective against the triply modified vancomycin requires a drug-resistant bacteria after other medications stopped working. But bacteria have Cl now evolved defenses against vancomycin, which works by inhibiting transpeptidase, HO NH OH Chlorobiphenyl an enzyme that catalyzes a cross-linking reOH group action bacteria use to build cell walls. O Scientists have recently modified vancoO OH mycin in various ways to boost its potency and discourage resistance. In fact, the U.S. O Food & Drug Administration recently apO proved three modified vancomycins: oritaO O Cl vancin, dalbavancin, and telavancin. Cl They are each made by semisyntheOH HO O O sis from vancomycin by chemical H H O H N N NHCH3 addition or modification of one or two N N N H H H H chemical groups. O OO Dale L. BoH NH Methylene H ger of Scripps substitution NH2 N (CH3)3N+ Research InOH 30-step total synthesis, which stitute and coO Quaternary OH workers have would be tough to carry out trimethylammonium HO now created industrially. group what could In this version of “By adding all the compobe the ultimate vancomycin vancomycin, three nents known to make it hard by modifying it in three ways modifications give for resistance to occur, Boger’s (Proc. Natl. Acad. Sci. USA 2017, the compound group has crafted perhaps the DOI: 10.1073/pnas.1704125114). three mechanisms quintessential glycopeptide The new version is more than of action. antibiotic” for today’s drug-re10,000-fold as potent as vansistant bacteria, says vancocomycin and about 250-fold as potent as mycin expert Gerry Wright of McMaster oritavancin against vancomycin-resistant University. The challenge of scaling up the enterococci bacteria. Boger and coworkers synthesis, even for preclinical and clinical believe it is also about 250-fold as potent studies, remains to be overcome, Wright as dalbavancin and telavancin but haven’t adds, although “industrial process chemists verified that yet. can be geniuses in reducing the number of One modification, a methylene group steps in a synthesis.” substituted for an amide carbonyl that Boger agrees that reducing synthetic difsome bacteria have learned to avoid, reficulty “is a problem solvable by the ingestores transpeptidase inhibition. Another nuity of chemistry.” He believes it might be modification, also present in oritavancin, is worthwhile to produce triply modified vanan added chlorobiphenyl group that grants comycin at any price for special cases, even the ability to inhibit another bacterial cellby total synthesis, but his group is working wall biosynthesis step, catalyzed by transto streamline the total synthesis and develglycosylase. The third change, an added op a semisynthesis.—STU BORMAN JUNE 5, 2017 | CEN.ACS.ORG | C&EN
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