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NPJ Biofilms Microbiomes. 2018 Feb 27;4:4. doi: 10.1038/s41522-018-0048-3. eCollection 2018.

Precision antimicrobial therapeutics: the path of least resistance?

Author information

1
1Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, MA 02115 USA.
2
2Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110 USA.
3
3Center for Women's Infectious Disease Research (CWIDR), Washington University School of Medicine, St. Louis, MO 63110 USA.
4
4Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110 USA.

Abstract

The emergence of drug-resistant pathogens has led to a decline in the efficacy of traditional antimicrobial therapy. The rise in resistance has been driven by widespread use, and in some cases misuse, of antibacterial agents in treating a variety of infections. A growing body of research has begun to elucidate the harmful effects of broad-spectrum antibiotic therapy on the beneficial host microbiota. To combat these threats, increasing effort is being directed toward the development of precision antimicrobial therapeutics that target key virulence determinants of specific pathogens while leaving the remainder of the host microbiota undisturbed. This includes the recent development of small molecules termed "mannosides" that specifically target uropathogenic E. coli (UPEC). Mannosides are glycomimetics of the natural mannosylated host receptor for type 1 pili, extracellular appendages that promotes UPEC colonization in the intestine. Type 1 pili are also critical for colonization and infection in the bladder. In both cases, mannosides act as molecular decoys which potently prevent bacteria from binding to host tissues. In mice, oral treatment with mannosides simultaneously clears active bladder infection and removes intestinal UPEC while leaving the gut microbiota structure relatively unchanged. Similar treatment strategies successfully target other pathogens, like adherent-invasive E. coli (AIEC), an organism associated with Crohn's disease (CD), in mouse models. While not without its challenges, antibiotic-sparing therapeutic approaches hold great promise in a variety of disease systems, including UTI, CD, otitis media (OM), and others. In this perspective we highlight the benefits, progress, and roadblocks to the development of precision antimicrobial therapeutics.

Conflict of interest statement

S.J.H. and J.W.J. have ownership interest in Fimbrion Therapeutics, and may benefit if the company is successful in marketing mannosides. The remaining authors declare no competing interests.

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