Asset Details
Do you wish to reserve the book?
A synthetic antibiotic class overcoming bacterial multidrug resistance
Hey, we have placed the reservation for you!
By the way, why not check out events that you can attend while you pick your title.
Oops! Something went wrong.
Looks like we were not able to place the reservation. Kindly try again later.
Are you sure you want to remove the book from the shelf?
A synthetic antibiotic class overcoming bacterial multidrug resistance
Do you wish to request the book?
A synthetic antibiotic class overcoming bacterial multidrug resistance
Please be aware that the book you have requested cannot be checked out. If you would like to checkout this book, you can reserve another copy
We have requested the book for you!
Your request is successful and it will be processed during the Library working hours. Please check the status of your request in My Requests.
Oops! Something went wrong.
Looks like we were not able to place your request. Kindly try again later.
Journal Article
A synthetic antibiotic class overcoming bacterial multidrug resistance
2021
Overview
The dearth of new medicines effective against antibiotic-resistant bacteria presents a growing global public health concern
1
. For more than five decades, the search for new antibiotics has relied heavily on the chemical modification of natural products (semisynthesis), a method ill-equipped to combat rapidly evolving resistance threats. Semisynthetic modifications are typically of limited scope within polyfunctional antibiotics, usually increase molecular weight, and seldom permit modifications of the underlying scaffold. When properly designed, fully synthetic routes can easily address these shortcomings
2
. Here we report the structure-guided design and component-based synthesis of a rigid oxepanoproline scaffold which, when linked to the aminooctose residue of clindamycin, produces an antibiotic of exceptional potency and spectrum of activity, which we name iboxamycin. Iboxamycin is effective against ESKAPE pathogens including strains expressing Erm and Cfr ribosomal RNA methyltransferase enzymes, products of genes that confer resistance to all clinically relevant antibiotics targeting the large ribosomal subunit, namely macrolides, lincosamides, phenicols, oxazolidinones, pleuromutilins and streptogramins. X-ray crystallographic studies of iboxamycin in complex with the native bacterial ribosome, as well as with the Erm-methylated ribosome, uncover the structural basis for this enhanced activity, including a displacement of the
m
2
6
A
2058
nucleotide upon antibiotic binding. Iboxamycin is orally bioavailable, safe and effective in treating both Gram-positive and Gram-negative bacterial infections in mice, attesting to the capacity for chemical synthesis to provide new antibiotics in an era of increasing resistance.
Structure-guided design and component-based synthesis are used to produce iboxamycin, a novel ribosome-binding antibiotic with potent activity against Gram-positive and Gram-negative bacteria.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 64/60
/ Anti-Bacterial Agents - chemical synthesis
/ Anti-Bacterial Agents - chemistry
/ Anti-Bacterial Agents - classification
/ Anti-Bacterial Agents - pharmacology
/ Bacteria
/ Clindamycin - chemical synthesis
/ Drug Resistance, Multiple, Bacterial - drug effects
/ Enzymes
/ Genes
/ Humanities and Social Sciences
/ Lincomycin - chemical synthesis
/ Methyltransferases - genetics
/ Methyltransferases - metabolism
/ Multidrug resistant organisms
/ Oxepins
/ Pyrans
/ rRNA (adenosine-2'-0'-)-methyltransferase
/ Science
/ Thermus thermophilus - drug effects
