mattodd
commented
2 months ago Nice new review from Laura Piddock et al. https://www.nature.com/articles/s41591-024-03218-w
Open Yuhang-CADD opened 2 months ago
mattodd
commented
2 months ago Nice new review from Laura Piddock et al. https://www.nature.com/articles/s41591-024-03218-w
Yuhang-CADD
commented
2 months ago https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)01867-1/fulltext
Brief Summary: The growing threat of AMR (especially among old people_50s and older, 70s worse) is threatening with drastic growth in MRSA mortality and GNB resistance to carbapenems. More AMR caused deaths are estimated (1.91M) by 2050. Regional and age differences matter. Call for global interventions on this issue with coordinated policies and investment in this field for better ABX development and infection control (reducing overuse of ABXs in agriculture and healthcare as was highlighted in O'Neil's systematic review back in 2016).
Yuhang-CADD
commented
2 months ago Nice new review from Laura Piddock et al. https://www.nature.com/articles/s41591-024-03218-w
Brief Summary: Pipeline of ABX development inadequate Lack of innovation and investment in new drug classes (also see this D Klug, M Todd et al) Companies and researchers withdrawing from the market/field (brain/moneydrain in ABX research). Push (CARB-X, NIH, etc) and Pull (UK subscription Model, US GAIN Act, etc) Incentives not working: high costs & low financial returns, support insufficient for ABX developmental circle (early-stage R&D no followups) and meet global scaled needs (no coordinated international actions) Global inequities in ABX access (income wise)[GARDP is working hard on making new ABX available in low-middle income regions]
Yuhang-CADD
commented
2 months ago
Yellow: on the make
Green: synthesized
Red: failed on synthesis
About the Pyridiniums: deteriorate upon vac-down, will have plenty of water after purification, will try Cyrotrap method (one last try) or abandon (considering their lowest tendency to be a good accumulator)
Yuhang-CADD
commented
2 months ago Due to the lack of AZ compounds in full length MurC, the interactions between one side chain of AZ scaffolds and the protein (truncated central domain) were missing. [Looking forward to Laura and Scott's Xstals!) which made the side chain modifications of AZ derivatives more difficult to predict.
Hypothesis on the side-chain interaction map:
Note: the pyrazolopyrimidine core and pyrazole side chain have been proven to bind to the MurC consistently the way described, details see (PDB: 6X9F, 6X9N, 8DOF)
Side-chain is represented by "G" and the linking group is represented by "Y".
In different structures, the size of G can vary, shortest within the proposed hydrophobic area, longest reaching the proposed hydrophilic area.
Structural validation:
AZ alcohols with nanomolar potency (functional groups to fit into the hydrophobic pocket on the G site and the extending alcohol to fit the hydrophobic pocket/just maintaining hydrophilic interactions)
AZ derivatives with micromolar potency (either due to extra charge that caused the compound harder to enter/pose in MurC the way AZ alcohols do, or lack of hydrophilic interactions from the extended end)
AZ rigid derivatives with bad potency [hydrophilic amine in the hydrophobic pocket or just completely does not fit in (TR1-4-BP)]
Furthermore, checking the original Hameed paper, all of the potent ones have such hydrophobic contacting group on the side chain and then extending to have a polar hydrophilic ending.
Final validation sets:
Especially
Yuhang-CADD
commented
2 months ago Warwick's contribution to the IC50s and Ki of 3rd_round_shipments_AZ_chapter2_Yuhang Aug 2024-2.pptx
Yuhang-CADD
commented
2 months ago Nice new review from Laura Piddock et al. https://www.nature.com/articles/s41591-024-03218-w
Advancing global antibiotic research, development and access
Brief Summary: Pipeline of ABX development inadequate Lack of innovation and investment in new drug classes (also see this D Klug, M Todd et al) Companies and researchers withdrawing from the market/field (brain/moneydrain in ABX research). Push (CARB-X, NIH, etc) and Pull (UK subscription Model, US GAIN Act, etc) Incentives not working: high costs & low financial returns, support insufficient for ABX developmental circle (early-stage R&D no followups) and meet global scaled needs (no coordinated international actions) Global inequities in ABX access (income wise)[GARDP is working hard on making new ABX available in low-middle income regions]
Achieving sustainable access to antibiotics is more than just a last mile challenge https://www.nature.com/articles/s41579-024-01083-5
The AMR Accelerator: from individual organizations to efficient antibiotic development partnerships
Date: Sep 10th 2024 Time: 2pm UK time other timezones
Place: https://ucl.zoom.us/j/91379419977
Recording:
Previous Meeting: #112 Who can come?: Anyone. No need to say anything unless you'd like to.
Apologies:
Decks: Please @opensourceantibiotics/murligase remember that if you share slides/info, to drag and drop those into a comment on this page, below. Very easy and saves @mattodd having to pester you.
Agenda:
Key things today are:
i) Multi-targeting compounds identified from Warwick and Atomwise collections. Updates on any new IC50 or crystallographic or microbiology data.
ii) New data from Warwick on the contributed AZ compounds (including MICs, retests of IC50s at a lower concentration). Also, any updates on AZ compounds vs TB? @LauraDS1
iii) Update on crystallographic data of AZ compound 4 (WYH9 compound) in Pae MurD ligase.
(please add if you'd like to prioritise anything)
1) Multi-targeting Compounds from the Warwick/NEU Enamine Collection and Atomwise Compounds
2) Multi-targeting Elaborated Fragments from Diamond Fragment Screen
3) Variants of AZ Compounds
These will include guanidinium and pyridinium derivatives to try to combat efflux.
4) New Protein Structures
No new structures to add to the PDB list.
5) De Novo Computational Modelling
@Yuhang-CADD has paused synthesis of @jhjensen2's originally-suggested compounds (last update was here while the AZ derivatives are being made.
6) CC4CARB Proposal (#93)
7) Misc/AOB
Last time @AJLloyd105 reported on the evaluation, enzymatically, of "double-headed" compounds containing uridine and ATP binders: . These were found to be binders and will be investigated further (need to upload deck). @AJLloyd105 to update as appropriate.
8) Mothballs (if no actions then these need to be linked in wiki and closed)
@mattodd is in the process of converting old items to the wiki
Next Meeting
Oct 8th 2pm UK time
L'esprit de l'escalier
If you'd like to follow up after the meeting, please comment below. You can also email, but please be clear if anything in the email should not be public domain - the default is always open.