cryoEM‐Guided Development of Antibiotics for Drug‐Resistant Bacteria

Belousoff, Matthew J.; Venugopal, Hari; Wright, Alexander; Seoner, Samuel; Stuart, Isabella; Stubenrauch, Christopher J.; Bamert, Rebecca S.; Lupton, David W.; Lithgow, Trevor

doi:10.1002/cmdc.201900042

Cited by 24 publications

(24 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These predictions can help to direct efforts when targeting the ribosome for the development of drugs to overcome the looming antibiotic crisis. 7 , 49 …”

Section: Discussionmentioning

confidence: 99%

“…This finding underlines the notation that these promising targets for new antibiotics could be addressed with drug-like ligands. ,, Further, also in the ribosomal binding site set, druggable pockets were contained (Table S4). These predictions can help to direct efforts when targeting the ribosome for the development of drugs to overcome the looming antibiotic crisis. , …”

Section: Discussionmentioning

confidence: 99%

“…These predictions can help to direct efforts when targeting the ribosome for the development of drugs to overcome the looming antibiotic crisis. 7,49 Notably, as DrugPred_RNA was trained with descriptors that can be calculated for both RNA and protein binding sites, it can also be used to score pockets that are formed by both types of macromolecules. An example is a pocket in the protozoal 80S ribosomal site that highly efficiently (LE = 0.41 kcal•mol −1 •heavy atom −1 ) binds to the drug-like molecule mefloquine (QED = 0.79) and was predicted to be druggable (Figure 9).…”

Section: ■ Conclusionmentioning

confidence: 99%

See 2 more Smart Citations

DrugPred_RNA—A Tool for Structure-Based Druggability Predictions for RNA Binding Sites

Rekand

Brenk

2021

J. Chem. Inf. Model.

View full text Add to dashboard Cite

RNA is an emerging target for drug discovery. However, like for proteins, not all RNA binding sites are equally suited to be addressed with conventional drug-like ligands. To this end, we have developed the structure-based druggability predictor DrugPred_RNA to identify druggable RNA binding sites. Due to the paucity of annotated RNA binding sites, the predictor was trained on protein pockets, albeit using only descriptors that can be calculated for both RNA and protein binding sites. DrugPred_RNA performed well in discriminating druggable from less druggable binding sites for the protein set and delivered predictions for selected RNA binding sites that agreed with manual assignment. In addition, most drug-like ligands contained in an RNA test set were found in pockets predicted to be druggable, further adding confidence to the performance of DrugPred_RNA. The method is robust against conformational and sequence changes in the binding sites and can contribute to direct drug discovery efforts for RNA targets.

show abstract

“…These predictions can help to direct efforts when targeting the ribosome for the development of drugs to overcome the looming antibiotic crisis. 7 , 49 …”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: ■ Conclusionmentioning

confidence: 99%

See 1 more Smart Citation

DrugPred_RNA—A Tool for Structure-Based Druggability Predictions for RNA Binding Sites

Rekand

Brenk

2021

J. Chem. Inf. Model.

View full text Add to dashboard Cite

show abstract

“…More than half of the antibiotics currently used inhibit protein synthesis by binding to the functional centers of the ribosome. Recently, important insights into the mechanism of these antibiotics have been obtained by X-ray crystallography and cryo-electron microscopy (Cryo-EM) analysis, opening the possibility of developing new molecules by structure-based drug design (29–36).…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Self-Resistance Mechanism to Dityromycin in the Streptomyces Producer Strain

Fabbretti

Çapuni

Giuliodori

et al. 2019

mSphere

View full text Add to dashboard Cite

Dityromycin is a peptide antibiotic isolated from the culture broth of the soil microorganism Streptomyces sp. strain AM-2504. Recent structural studies have shown that dityromycin targets the ribosomal protein S12 in the 30S ribosomal subunit, inhibiting translocation. Herein, by using in vitro protein synthesis assays, we identified the resistance mechanism of the producer strain to the secondary metabolite dityromycin. The results show that the self-resistance mechanism of the Streptomyces sp. strain AM-2504 is due to a specific modification of the ribosome. In particular, two amino acid substitutions, located in a highly conserved region of the S12 protein corresponding to the binding site of the antibiotic, were found. These mutations cause a substantial loss of affinity of the dityromycin for the 30S ribosomal subunit, protecting the producer strain from the toxic effect of the antibiotic. In addition to providing a detailed description of the first mechanism of self-resistance based on a mutated ribosomal protein, this work demonstrates that the molecular determinants of the dityromycin resistance identified in Streptomyces can be transferred to Escherichia coli ribosomes, where they can trigger the same antibiotic resistance mechanism found in the producer strain. IMPORTANCE The World Health Organization has identified antimicrobial resistance as a substantial threat to human health. Because of the emergence of pathogenic bacteria resistant to multiple antibiotics worldwide, there is a need to identify the mode of action of antibiotics and to unravel the basic mechanisms responsible for drug resistance. Antibiotic producers’ microorganisms can protect themselves from the toxic effect of the drug using different strategies; one of the most common involves the modification of the antibiotic’s target site. In this work, we report a detailed analysis of the molecular mechanism, based on protein modification, devised by the soil microorganism Streptomyces sp. strain AM-2504 to protect itself from the activity of the peptide antibiotic dityromycin. Furthermore, we demonstrate that this mechanism can be reproduced in E. coli, thereby eliciting antibiotic resistance in this human commensal bacterium.

show abstract

“…The drug developers' solution to this scenario involves attempts to design drugs that would hit their target in such a way that any change in the target would result in loss-of-function. An example of this is the way in which linezolid binds to bacterial ribosomes: only one other escape conformation is possible in the ribosome and a second 'linezolid-like' drug has been proposed to block this site [55].…”

Section: Box 1 Mechanisms For Acquiring An Amr Phenotypementioning

confidence: 99%

Targeting bacterial outer-membrane remodelling to impact antimicrobial drug resistance

Rosas

Lithgow

2022

Trends in Microbiology

Self Cite

View full text Add to dashboard Cite

The cell envelope is essential for survival and adaptation of bacteria. Bacterial membrane proteins include the major porins that mediate the influx of nutrients and several classes of antimicrobial drugs. Consequently, membrane remodelling is closely linked to antimicrobial resistance (AMR). Knowledge of bacterial membrane protein biogenesis and turnover underpins our understanding of bacterial membrane remodelling and the consequences that this process have in the evolution of AMR phenotypes. At the population level, the evolution of phenotypes is a reversible process, and we can use these insights to deploy evolutionary principles to resensitize bacteria to existing antimicrobial drugs. In our opinion, fundamental knowledge is opening a new way of thinking towards sustainable solutions to the mounting crisis in AMR. Here we discuss what is known about outer-membrane remodelling in bacteria and how the process could be targeted as a means to restore sensitivity to antimicrobial drugs. Bacteriophages are highlighted as a powerful means to exert this control over membrane remodelling but they require careful selection so as to reverse, and not exacerbate, AMR phenotypes. Antimicrobial resistance is a phenotypeThe global impact in loss of human life from increases in AMR has distracted many interested parties from the obvious, simple message that a key definition of AMR is that it is a phenotype. As with other phenotypes, it is a transient description of a given population of bacteria (or fungi, or parasites, but here we focus on bacteria) which is subject to evolution, based on selection under a given set of selective pressures. When we push the evolution of a bacterial population by increasing the exposure to antimicrobials we are selecting for an AMR phenotype. Any strategy that would slow or select against the AMR phenotype would be a better idea.

show abstract

cryoEM‐Guided Development of Antibiotics for Drug‐Resistant Bacteria

Cited by 24 publications

References 34 publications

DrugPred_RNA—A Tool for Structure-Based Druggability Predictions for RNA Binding Sites

DrugPred_RNA—A Tool for Structure-Based Druggability Predictions for RNA Binding Sites

Characterization of the Self-Resistance Mechanism to Dityromycin in the Streptomyces Producer Strain

Targeting bacterial outer-membrane remodelling to impact antimicrobial drug resistance

Contact Info

Product

Resources

About