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.
Highlights
Antibiotics are considered the standard of care for the treatment of most bacterial infections caused by drug-susceptible organisms
The worldwide spread of drug-resistant bacterial pathogens has greatly limited the repertoire of antibiotics available to effectively treat patients
Clinicians are becoming increasingly reliant on last-line antimicrobial agents to treat a growing number of common bacterial infections
Summary
Antibiotics are considered the standard of care for the treatment of most bacterial infections caused by drug-susceptible organisms. This therapeutic rationale is currently being tested in a Phase host defenses, promoting ongoing infection. Infections are the leading cause of hospital-acquired diarrhea and can be highly recurrent, resulting in increased of the type 1 and F17-like adhesins (FimH and UclD, respectively) exposure to antibiotics This has led to a large number of were shown to bind to distinct micro-habitats within the colonic antibiotic-resistant isolates worldwide. Several groups have identified and demonstrated efficacy for promising glycomimetic compounds targeting LecA/B.54,55 The company GlycoMimetics has reported the discovery of a dual LecA/B antagonist, GM-1051 which is in preclinical testing to treat and prevent P. aeruginosa infection in 2009,54 but no additional information has been published since that time
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