Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Synthetic macrolides overcoming MLSK-resistant pathogens.
Journal, issue, pages	Cell Discov, Vol. 10, Issue 1, Page 75, Year 2024
Publish date	Jul 11, 2024
Authors	Cong-Xuan Ma / Ye Li / Wen-Tian Liu / Yun Li / Fei Zhao / Xiao-Tian Lian / Jing Ding / Si-Meng Liu / Xie-Peng Liu / Bing-Zhi Fan / Li-Yong Liu / Feng Xue / Jian Li / Jue-Ru Zhang / Zhao Xue / Xiao-Tong Pei / Jin-Zhong Lin / Jian-Hua Liang /
PubMed Abstract	Conventional macrolide-lincosamide-streptogramin B-ketolide (MLSK) antibiotics are unable to counter the growing challenge of antibiotic resistance that is conferred by the constitutive methylation ...Conventional macrolide-lincosamide-streptogramin B-ketolide (MLSK) antibiotics are unable to counter the growing challenge of antibiotic resistance that is conferred by the constitutive methylation of rRNA base A2058 or its G2058 mutation, while the presence of unmodified A2058 is crucial for high selectivity of traditional MLSK in targeting pathogens over human cells. The absence of effective modes of action reinforces the prevailing belief that constitutively antibiotic-resistant Staphylococcus aureus remains impervious to existing macrolides including telithromycin. Here, we report the design and synthesis of a novel series of macrolides, featuring the strategic fusion of ketolide and quinolone moieties. Our effort led to the discovery of two potent compounds, MCX-219 and MCX-190, demonstrating enhanced antibacterial efficacy against a broad spectrum of formidable pathogens, including A2058-methylated Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and notably, the clinical Mycoplasma pneumoniae isolates harboring A2058G mutations which are implicated in the recent pneumonia outbreak in China. Mechanistic studies reveal that the modified quinolone moiety of MCX-190 establishes a distinctive secondary binding site within the nascent peptide exit tunnel. Structure-activity relationship analysis underscores the importance of this secondary binding, maintained by a sandwich-like π-π stacking interaction and a water-magnesium bridge, for effective engagement with A2058-methylated ribosomes rather than topoisomerases targeted by quinolone antibiotics. Our findings not only highlight MCX-219 and MCX-190 as promising candidates for next-generation MLSK antibiotics to combat antibiotic resistance, but also pave the way for the future rational design of the class of MLSK antibiotics, offering a strategic framework to overcome the challenges posed by escalating antibiotic resistance.
External links	Cell Discov / PubMed:38992047 / PubMed Central
Methods	EM (single particle)
Resolution	2.53 - 3.6 Å
Structure data	38873 8y36 EMDB-38873, PDB-8y36: cryo-EM structure of Staphylococcus aureus(ATCC 29213) 50S ribosome in complex with MCX-190. Method: EM (single particle) / Resolution: 2.65 Å 38874 8y37 EMDB-38874, PDB-8y37: Cryo-EM structure of Staphylococcus aureus (15B196) 50S ribosome in complex with MCX-190. Method: EM (single particle) / Resolution: 2.53 Å 38875 8y38 EMDB-38875, PDB-8y38: Cryo-EM structure of Staphylococcus aureus 70S ribosome (strain 15B196) in complex with MCX-190. Method: EM (single particle) / Resolution: 2.58 Å 38876 8y39 EMDB-38876, PDB-8y39: cryo-EM structure of Staphylococcus aureus(ATCC 29213) 70S ribosome in complex with MCX-190. Method: EM (single particle) / Resolution: 3.6 Å
Chemicals	PDB-1d6g: MOLECULAR COMPLEX OF CHOLECYSTOKININ-8 AND N-TERMINUS OF THE CHOLECYSTOKININ A RECEPTOR BY NMR SPECTROSCOPY ChemComp-MG: Unknown entry ChemComp-HOH: WATER
Source	staphylococcus aureus (bacteria)
Keywords	RIBOSOME / antibiotics / antibiotic / MLSBK-resistant