Marvin Miller: siderophores, Trojan horses, and the tuberculosis program

1977 — today

Smuggling drugs through the iron door: The medicinal chemist of this record is Marvin J. Miller, who joined the Notre Dame faculty in 1977 and held the George and Winifred Clark chair from 1996. His laboratory's documented core achievement is synthetic: the first syntheses of a shelf of siderophores — the small molecules bacteria secrete to steal iron from their hosts — aerobactin, arthrobactin, schizokinen, several mycobactins, foroxymithine and analogs among them, in his department's own summary. On that foundation the laboratory built its strategy against drug-resistant infection: siderophore-antibiotic conjugates, synthetic "sideromycins" that hitch an antibiotic to the iron carrier the bacterium actively imports, smuggling the drug through the cell's own iron door — the Trojan-horse program, in the laboratory's phrase. The tuberculosis work drew the program's largest documented support: in the spring of 2010 Miller received a $1.9 million National Institutes of Health grant to advance the laboratory's lead small-molecule anti-tuberculosis agents — nanomolar inhibitors of multidrug-resistant and extensively drug-resistant strains — through in vivo preclinical development, in collaboration with the NIH, the Eli Lilly TB Initiative, Dow AgroSciences and university partners here and abroad; the program's later published work includes the 2021 EMBO Molecular Medicine paper, with Miller among its authors, reporting that dual inhibition of the tuberculosis bacillus's terminal oxidases eradicates antibiotic-tolerant bacteria. The measures of the career are printed as their dated sources give them: more than 260 peer-reviewed publications and 20 patents in the university's 2011 award account; more than 300 publications and more than 25 United States patents in 2016, when the American Chemical Society's Division of Medicinal Chemistry inducted him into its Hall of Fame.

Sources:

1. Department of Chemistry and Biochemistry, University of Notre Dame, Marvin Miller profile — the first syntheses of aerobactin, arthrobactin, schizokinen, several mycobactins and foroxymithine; the siderophore-antibiotic conjugate program; Lin, Ghosh, Möllmann and Miller, "Synthetic sideromycins," Biometals 32 (2019): 425–451.
2. University of Notre Dame news (spring 2010) — the $1.9 million NIH grant; the lead agents as nanomolar inhibitors of multidrug-resistant and extensively drug-resistant tuberculosis; the Trojan-horse rationale; the NIH, Lilly TB Initiative and Dow AgroSciences collaborations; Lee et al., EMBO Molecular Medicine 13 (2021), the terminal-oxidase paper among the laboratory's listed publications.
3. Graduate School, University of Notre Dame (2011) — Miller's 2011 Burns Award account: at Notre Dame from 1977, Clark Professor from 1996, more than 260 publications and 20 patents, the figures as then given.
4. Harper Cancer Research Institute news (5 August 2016) — Miller's induction into the ACS Division of Medicinal Chemistry Hall of Fame; more than 300 peer-reviewed publications and more than 25 United States patents, as then given; nearly forty years of medicinal chemistry.