Troy Lister

The Bug Battler

Medicinal chemist takes unconventional approach to battling bacteria

As a boy in Australia, Troy Lister always liked building things—intricate model airplanes or complex electronic circuits—and knew he’d end up working with his hands. Today, his tinkering might be on the microscopic scale, but its impact is definitely bigger. Lister is trying to construct molecules that could stop our worst bacterial nightmare.

In the past 50 years, only two new classes of antibiotics have made it onto the market—every other “novel” microbe killer has come from tweaking older molecules. So swiftly are bacteria outwitting us that, in 2014, the World Health Organization warned we were on the verge of a post-antibiotic world.

Lister is trying to prevent that nightmare scenario in a rather unconventional way.

As head of chemistry at the tiny Cambridge, Mass.-based start-up Spero Therapeutics, Lister isn’t designing compounds that directly kill bacteria. Instead, Spero’s molecules weaken bacterial defenses so that infections are less aggressive and older antibiotics can be used at lower doses to completely knock them out.

The most advanced compounds hobble the highly polar outer membrane used by gram-negative bacteria to repel large, lipid-loving antibiotics. Another effort targets a signaling protein that disarms Pseudomonas aeruginosa, making it easier for the immune system or an antibiotic to clear the infection.

Few companies have been willing to chase molecules that fall outside the traditional antibiotic paradigm. “It’s a much tougher concept to understand clinically and to develop drugs for,” Lister says. “But you’re not going to significantly advance the field if you’re only making incremental improvements over what’s out there.” – Lisa M. Jarvis

Vital Stats

Current Affiliation: Spero Therapeutics

Age: 35

Ph.D. alma mater: Flinders University, Adelaide, Australia

Talent: Developing molecules to weaken bacterial defenses.

Scientific role model: Richard Feynman. The quote that made him most want to emulate Feynman? “Study hard what interests you the most in the most undisciplined, irreverent, and original manner possible.”

Three Most Important Papers By Lister:

“Design, Synthesis, and Biological Evaluation of Platensimycin Analogues with Varying Degrees of Molecular Complexity” (J. Am. Chem. Soc. 2008, DOI: 10.1021/ja8044376)

“Cascade Reactions Involving Formal [2+2] Thermal Cycloadditions: Total Synthesis of Artochamins F, H, I, and J” (Angew. Chem. Int. Ed. 2007, DOI: 10.1002/anie.200702363)

“Total Synthesis of Auripyrone A” (Angew. Chem. Int. Ed. 2006, DOI: 10.1002/anie.200504573)

Research At A Glance

A tough-to-penetrate outer membrane has made it nearly impossible for chemists to find new classes of drugs to combat gram-negative bacteria. As head of chemistry at Spero Therapeutics, Lister is working on molecules called potentiators, which weaken that highly polar barrier, allowing traditional antibiotics to sneak in and do their killing.
A tough-to-penetrate outer membrane has made it nearly impossible for chemists to find new classes of drugs to combat gram-negative bacteria. As head of chemistry at Spero Therapeutics, Lister is working on molecules called potentiators, which weaken that highly polar barrier, allowing traditional antibiotics to sneak in and do their killing.

Credit: CDC/Spero Therapeutics/C&EN

Luke Lavis
Matt MacDonald
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