Precision antimicrobial therapeutics: the path of least resistance?

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.

Fig. 1

Potential effects of oral mannoside and antibiotic treatment on the intestinal UPEC population. a Intestinal UPEC reach the bladder and can cause UTI after being shed in the feces. b Oral mannoside treatment targets and reduces the UPEC intestinal population and simultaneously treats and clears UTI in the bladder with minimal effects on the overall structure/diversity of the gut microbiota. c Conversely, oral treatment with clinically relevant broad-spectrum antibiotics, like ciprofloxacin, can treat and clear UTI but reduces the overall abundance and diversity of the gut microbiota. The resulting intestinal inflammation caused by antibiotic treatment may promote intestinal E. coli colonization (including UPEC) and thus can lead to increase UPEC fecal shedding, promoting recurrent UTI

Fig. 2

Precision therapeutics target a specific organism while leaving the remainder a microbiota community untouched. Artist rendering of how mannoside treatment (compound from prescription bottle) selectively extirpates UPEC from the gut microbiota