The van den Akker Lab

Structural Biology And Drug Discovery Approaches On Bacterial Cell Wall Targets

The van den Akker lab carries out structure-function and inhibitor design studies to combat antibiotic resistance. We study known drug targets and also aim to discover new Achilles' heel opportunities: the main targets are proteins involved in peptidoglycan metabolism including penicillin-binding proteins (PBPs), β-lactamases, and lytic transglycosylases among others. We explore mechanism-based reaction-coordinate inhibitors and also employ fragment-based ligand discovery approaches. Key techniques used are protein crystallography, biophysical tools to probe ligand binding (DSF and SPR), computational methods (in silico docking and molecular dynamics simulations), and enzymatic assays while collaborating with expert microbiologists, biochemists, medicinal chemists, and pharmaceutical companies.

Additional non-antibiotic resistance drug-discovery related projects include developing and studying new agents to prevent pre-term birth (NIH funded collaboration with Dr. Sam Mesiano) and developing nitrosylation modulators (NIH funded collaboration with Dr. Jonathan Stamler).


Latest News


Our manuscript describing the crystallographic characterization of the KPC β-lactamase variants D179N and D179Y which confer resistance to ceftazidime/avibactam resistance has been published in AAC

3/29/22

https://pubmed.ncbi.nlm.nih.gov/35341315/

This work was in collaboration with Drs. Robert Bonomo, Shields, Nguyen, and Clancy.

Our manuscript describing the characterization of the KPC β-lactamases D179Y variant that confers resistance to ceftazidime/avibactam resistance has been published online in AAC

3/22/22

https://pubmed.ncbi.nlm.nih.gov/35311523/

This work was in collaboration with Drs. Robert Bonomo, Shields, Nguyen, and Clancy.

Our manuscript describing the inhibition of PBP3 by the boronic acid inhibitor vaborbactam has been published online in PLOS ONE

10/16/21

https://pubmed.ncbi.nlm.nih.gov/34653211/

This work was in collaboration with Dr. Robert Bonomo.

Our manuscript describing a novel γ-lactam PBP3 inhibitor that is effective against several MDR pathogens has been published online in Eur. J. Med. Chem.

4/29/21

https://pubmed.ncbi.nlm.nih.gov/33933754/

This work was in collaboration with Drs. Robert Bonomo and Mark Plummer.

Our manuscript describing a novel soluble guanylyl cyclase activator (Runcaciguat) has been published Online in J. Med. Chem.

4/20/20

https://pubmed.ncbi.nlm.nih.gov/33872507/

This work was in collaboration with Bayer AG, Pharmaceuticals

Our manuscript describing the Turnover Chemistry and Structural Characterization of a Lytic Transglycosylase of Campylobacter jejuni via crystallography, biophysical, and mass spectrometry methods was just published online

3/22/21

https://pubmed.ncbi.nlm.nih.gov/33749238/

This work was in collaboration with Drs. Shahriar Mobashery and Jun Lin.

Our manuscript describing the binding of the dual-target diazabicyclooctane inhibitors to the penicillin-binding protein 2 and 3 of the pathogen Pseudomonas aeruginosa via crystallography and biophysical methods was just published online

2/16/21

https://pubmed.ncbi.nlm.nih.gov/33593978/

This work was in collaboration with Wockhard Research Center and Dr. Robert Bonomo.

Our manuscript describing the microbiological, biochemical, and structural characterization of a γ-lactam siderophore PBP inhibitor was just published online

6/20/20

https://pubmed.ncbi.nlm.nih.gov/32420736/

This work was in collaboration with Drs. Robert Bonomo and Mark Plummer. Article featured on the Cover.

Congratulations to Snigdha and Ha for being accepted and entering into PhD programs and Radhika for being accepted and entering into Medical School!

7/1/20

Our manuscript describing the binding of the antibiotic ceftobiprole to the penicillin-binding protein 3 of the pathogen Pseudomonas aeruginosa via crystallography and biophysical methods was just published online

3/9/20

https://www.ncbi.nlm.nih.gov/pubmed/32152075

This work was in collaboration with Basilea Pharmaceutica International Ltd. and Dr. Robert Bonomo.

The lab receiving R21 NIH grant funding for a new project on fragment-based approaches to develop new inhibitors of lytic transglycosylases. Such inhibitors could potentiate b-lactam antibiotics.

12/30/19

The research of the van den Akker lab was recently featured in the annual research update of the Ohio Supercomputer Center.

12/1/19

https://www.osc.edu/sites/default/files/page-files/2019%20Research%20Report.pdf
This work featured an all-atom 1-μs molecular dynamics simulation of the doughnut-shaped lytic transglycosylase enzyme and its peptidoglycan substrate and was published last year.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197136

A multi-lab collaborative manuscript was accepted for publication entitled "A standard numbering scheme for class C β-lactamases".

11/8/19

https://aac.asm.org/content/early/2019/11/05/AAC.01841-19.long

A manuscript was accepted for publication on the crystal structure of doripenem in complex to a deacylation deficient mutant of the OXA-48 β-lactamase (collaboration with Dr. Papp-Wallace lab).

https://www.mdpi.com/2079-6382/8/3/145