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.

Rapid molecular detection of macrolide resistance

“…c Mef(A) RPA results for S. pneumoniae and E. faecium. For panels b and c, DNA concentration in raw lysates was measured and total amount of DNA loaded into each reaction is indicated, and lines are labeled with species name and whether they are known mef(A) positive (+) or negative (−) includes the microbiome [57][58][59][60] and associated mediators of antimicrobial resistance [61]. Because the microbiome is a dynamic entity in which antimicrobial resistance genes are shared among members [53], it is clinically vital to monitor levels of antibiotic resistance genes in commensal bacteria of healthy individuals that may contribute to more severe disease.…”

A shear stress micromodel of urinary tract infection by the Escherichia coli producing Dr adhesin

“…The prevalence of recurrent UTIs motivates the search for small-molecule binding inhibitors that block the attachment or remove E. coli from the urinary tract [36]. One such lead compound is chloramphenicol (Cm), a popular antibiotic that was shown to compete with receptor binding by DraE in stationary systems [15,37].…”

Attenuation of Pseudomonas aeruginosa Quorum Sensing by Natural Products: Virtual Screening, Evaluation and Biomolecular Interactions

“…Globally, multi-drug resistant infections kill almost 700,000 people per year and it is predicted that it would increase up to 10 million deaths per year by 2050 [1]. This is due to the misuse and overuse of existing antimicrobials in humans, animals and plants, resulting in the development of multi-drug resistant (MDR) pathogenic bacteria [2].…”