Physiological cost of antibiotic resistance: Insights from a ribosome variant in bacteria DOI Creative Commons
Eun Chae Moon, Tushar Modi, Dong-yeon D. Lee

et al.

Science Advances, Journal Year: 2024, Volume and Issue: 10(46)

Published: Nov. 15, 2024

Antibiotic-resistant ribosome variants arise spontaneously in bacterial populations; however, their impact on the overall physiology remains unclear. We studied naturally arising antibiotic-resistant L22* variant of Bacillus subtilis and identified a Mg 2+ -dependent physiological cost. Coculture competition experiments show that limitation hinders growth more than wild type (WT), even under antibiotic pressure. This disadvantage cells is not due to lower abundance but rather reduced intracellular levels. Coarse-grained elastic-network modeling conformational dynamics suggests ribosomes associate tightly with when compared WT. combined structural experimental measurements steady-state model predict cellular adenosine 5′-triphosphate (ATP) levels, which also depend . Experiments confirmed predicted ATP drop limitation, while WT were less affected. Intracellular for finite pool can thus suppress establishment an variant.

Language: Английский

Atomistic Prediction of Structures, Conformational Ensembles and Binding Energetics for the SARS-CoV-2 Spike JN.1, KP.2 and KP.3 Variants Using AlphaFold2 and Molecular Dynamics Simulations: Mutational Profiling and Binding Free Energy Analysis Reveal Epistatic Hotspots of the ACE2 Affinity and Immune Escape DOI
Nishank Raisinghani, Mohammed Alshahrani,

Grace Gupta

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 10, 2024

Abstract The most recent wave of SARS-CoV-2 Omicron variants descending from BA.2 and BA.2.86 exhibited improved viral growth fitness due to convergent evolution functional hotspots. These hotspots operate in tandem optimize both receptor binding for effective infection immune evasion efficiency, thereby maintaining overall fitness. lack molecular details on structure, dynamics energetics the latest FLiRT FLuQE with ACE2 antibodies provides a considerable challenge that is explored this study. We combined AlphaFold2-based atomistic predictions structures conformational ensembles Spike complexes host dominant JN.1, KP.1, KP.2 KP.3 examine mechanisms underlying role balancing antibody evasion. Using ensemble-based mutational scanning spike protein residues computations affinities, we identified energy characterized basis epistatic couplings between results suggested existence interactions sites at L455, F456, Q493 positions enable protect restore affinity while conferring beneficial escape. To escape mechanisms, performed structure-based profiling several classes displayed impaired neutralization against BA.2.86, KP.3. confirmed experimental data harboring L455S F456L mutations can significantly impair neutralizing activity class-1 monoclonal antibodies, effects mediated by facilitate subsequent convergence Q493E changes rescue binding. Structural energetic analysis provided rationale showing BD55-5840 BD55-5514 bind different epitopes retain efficacy all examined support notion may favor emergence lineages combinations involving mediators control balance high

Language: Английский

Citations

5
Physiological cost of antibiotic resistance: Insights from a ribosome variant in bacteria DOI Creative Commons
Eun Chae Moon, Tushar Modi, Dong-yeon D. Lee

et al.

Science Advances, Journal Year: 2024, Volume and Issue: 10(46)

Published: Nov. 15, 2024

Antibiotic-resistant ribosome variants arise spontaneously in bacterial populations; however, their impact on the overall physiology remains unclear. We studied naturally arising antibiotic-resistant L22* variant of Bacillus subtilis and identified a Mg 2+ -dependent physiological cost. Coculture competition experiments show that limitation hinders growth more than wild type (WT), even under antibiotic pressure. This disadvantage cells is not due to lower abundance but rather reduced intracellular levels. Coarse-grained elastic-network modeling conformational dynamics suggests ribosomes associate tightly with when compared WT. combined structural experimental measurements steady-state model predict cellular adenosine 5′-triphosphate (ATP) levels, which also depend . Experiments confirmed predicted ATP drop limitation, while WT were less affected. Intracellular for finite pool can thus suppress establishment an variant.

Language: Английский

Citations

2