Focco van den Akker | Cleveland Center for Membrane & Structural Biology

Associate Professor, Department of Biochemistry, School of Medicine

Director, Department of Biochemistry, Research Honors Track Program

Research Information

Research Interests

The van den Akker lab focuses on structure-function and inhibitor design studies to combat antibiotic resistance. Our research investigates known drug targets while also aiming to discover new "Achilles' heel" opportunities within bacterial systems. Our primary targets include proteins involved in peptidoglycan metabolism, such as penicillin-binding proteins (PBPs), beta-lactamases, and lytic transglycosylases. We employ mechanism-based inhibitors and fragment-based ligand discovery approaches. We utilize a suite of techniques that includes protein crystallography, biochemical and biophysical tools to probe ligand binding (DSF and SPR), and computational methods such as in silico docking and molecular dynamics simulations. Through collaborations with microbiologists, medicinal chemists, and pharmaceutical partners, we aim to translate these molecular insights into potential therapeutics. In addition to small molecule design, we maintain an active project utilizing AI for protein therapeutic design.

With 79 peer-reviewed scientific articles and extensive experience as an NIH grant reviewer, I am deeply involved in the application of rigor in science. Furthermore, I developed a scientific rigor validation tool and have long led instructional efforts on scientific methods, reproducibility, and the navigation of conflicts of interest. My educational efforts span the undergraduate, MSc, PhD, and MD levels, with a broader interest in science advocacy and information literacy.

For a list of major publications and research support, please visit my ORCID profile.

I teach in the following courses:

BIOC 501 Biochemical and Cellular Techniques for Biotechnology (co-course director)
BIOC 334/434 Structural and Computational Biology
BIOC 101 Frontiers in Biochemistry

As director of the Research Honors program, I am also course director of BIOC 285 Honors Readings in Biochemistry.

Research Projects

van den Akker Lab Website

Publications

Publication Date

Fri, 11/03/2023 - 12:00

For my up-to-date list of publications, visit my NCBI's My Bibliography.

Mack, A.R., Kumar, V., Bethel, C., Taracila, M.A., Miller, B., Uehara, T., Six, D., Papp-Wallace, K.M., van den Akker, F., Bonomo, R.A. "Structure and mechanism of taniborbactam inhibition of the cefepime-hydrolyzing, partial R2-loop deletion Pseudomonas-derived cephalosporinase variant PDC-88." Antimicrob Agents Chemother. 2025 Jul 2;69(7):e0007825.
Boorman, J., Zeng, X., Lin, J., van den Akker, F. (2024) "Structural insights into peptidoglycan glycosidase EtgA binding to the inner rod protein EscI of the type III secretion system via a designed EscI-EtgA fusion protein." Protein Sci. Mar;33(3):e4930. doi: 10.1002/pro.4930.
Mack, A.R.*, Vijay Kumar, V.*, Taracila, M.A., Mojica, M.F., O'Shea,, M., Schinabeck, W., Silver, G., Hujer, A.M., Papp-Wallace, K.M., Chen, S., Haider, S., Caselli, E., Prati, F., van den Akker, F.#, Bonomo, R.A.# (2023) "Natural protein engineering in the Ω-loop: the role of Y221 in ceftazidime and ceftolozane resistance in Pseudomonas-derived cephalosporinase." Antimicrob Agents Chemother. Oct 18:e0079123.
Alsenani, T.A., Viviani, S.L., Papp-Wallace, K.M., Bonomo, R.A., van den Akker, F. (2023) "Exploring avibactam and relebactam inhibition of Klebsiella pneumoniae carbapenemase D179N variant: role of the Ω loop-held deacylation water." Antimicrob Agents Chemother. e0035023.
Kumar, V., Boorman, J., Greenlee, W.J., Zeng, X., Lin, J., van den Akker, F. (2023) "Exploring the inhibition of the soluble lytic transglycosylase Cj0843c of Campylobacter jejuni via targeting different sites with different scaffolds." Protein Sci. e4683.
Zhou, H.L., Hausladen, A.A., Anand, P., Rajavel, M., Stomberski, C.T., Zhang, R., Premont, R.T., Greenlee, W.J., van den Akker, F., Stamler, J.S. 2023) "Identification of a Selective SCoR2 Inhibitor That Protects Against Acute Kidney Injury." J. Med. Chem. 66(8):5657-5668.
Alsenani, T.A., Viviani, S.L., Kumar, V., Taracila, M.A., Bethel, C.R., Barnes, M.D., Papp-Wallace, K.M., Shields, R.K., Nguyen, M.H., Clancy, C.J., Bonomo, R.A., van den Akker, F. (2022) "Structural characterization of the D179N and D179Y variants of KPC-2 β-lactamase: Ω loop destabilization as a mechanism of resistance to ceftazidime/avibactam." Antimicrob Agents Chemother. E0241421.
Taracila, M.A., Bethel, C.R., Hujer, A.M., Papp-Wallace, K.M., Barnes, M.D., Rutter, J.D., VanPelt, J., Shurina, B.A., van den Akker, F., Clancy, C.J., Nguyen, M.H., Cheng, S., Shields, R.K., Page, R.C., and Bonomo, R.A. (2022) "Different Conformations Revealed by Nuclear Magnetic Resonance (NMR) Underlie Resistance to Ceftazidime/Avibactam and Susceptibility to Meropenem and Imipenem among D179Y Variants of KPC -lactamase." Antimicrob Agents Chemother. E0212421.
Kumar, V., Viviani, S.L., Ismail, J., Agarwal, S., Bonomo, R.A., van den Akker, F. (2021) "Structural analysis of the boronic acid β-lactamase inhibitor vaborbactam binding to Pseudomonas aeruginosa penicillin-binding protein 3." PLoS One 2021 16(10): e0258359.
Goldberg, J., Kumar, V., Spencer, E., Hoyer, D., Marshall, S., Hujer, A., Hujer, K., Bethel, C., Papp-Wallace, K.M., Perez, F., Jacobs, M., van Duin, D., Kreiswirth, B., van den Akker, F.*, Plummer, M.*, Bonomo, R.A.* (2021) "A γ-Lactam Siderophore Antibiotic Effective Against Multidrug-Resistant Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter spp." Eur. J. Med. Chem. 220, 113436.
Kumar, V., Mathure, S.A., Lee, M., Boorman, J., Zeng, X., Lin, J., Hesek, D., Mobashery, S., van den Akker, F. (2021) "Turnover chemistry and structural characterization of the Cj0843c lytic transglycosylase of Campylobacter jejuni." Biochemistry, 60, 1133-1144.
Hahn, M.G., Lampe, T., Sheikh, S. Griebenow, N., Woltering, E., Schlemmer, K.-H., Dietz, L., Gerisch, M., Wunder, F., Becker-Pelster, E.-M., Modritzki, T., Tinel, H., Knorr, A., Kern, A., Lang, D., Hüser, J., Schomber, T., Benardeau, A., Eitner, F., Trübel, H., Mittendorf, J., Kumar, V., van den Akker, F., Schaefer, M., Geiss, V., Sandner, P., Stasch, J.-H., (2021) "Discovery of the Soluble Guanylate Cyclase Activator Runcaciguat" (BAY 1101042). J. Med. Chem. 64, 5323-5344.
Rajavel, M., Kumar, V., Nguyen, H., Wyatt, J., Marshall, S. H., Papp-Wallace, K. M., Deshpande, P., Bhavsar, S., Yeole, R., Bhagwat, S., Patel, M., Bonomo, R. A., and van den Akker, F. (2021)
"Structural Characterization of Diazabicyclooctane beta-Lactam "Enhancers" in Complex with Penicillin-Binding Proteins PBP2 and PBP3 of Pseudomonas aeruginosa"
mBio 12, e03058-03020.
Goldberg, J.A., Nguyen, A., Kumar, V., Spencer, E.J., Hoyer, D., Marschall, E.K., Cmolik, A., O'Shea, M., Marshall, S.H., Hujer, A.M., Hujer, K.M., Rudin, S.D., Domitrovic, N., Bethel, C.R., Papp-Wallace, K.M., Logan, L.K., Perez, F., Jacobs, M.R., van Duin, D., Kreiswirth, B.M., Bonomo, R.A.*, Plummer, M.S.*, van den Akker F.* (2020), "A gamma-Lactam Siderophore Antibiotic Effective Against Multidrug-Resistant Gram-Negative Bacilli"
J. Med. Chem. 63, 5990-6002.
Kumar, V., Tang, C., Bethel C.R., Papp-Wallace K.M., Wyatt, J., Desarbre, E., Bonomo, R.A., van den Akker F. "Structural insights into ceftobiprole inhibition of Pseudomonas aeruginosa penicillin-binding protein 3". Antimicrob Agents Chemother.
Papp-Wallace, K.M.*, Kumar, V., Zeiser, E.T., Becka, S.A., van den Akker F. * (2019) "Structural Analysis of The OXA-48 Carbapenemase Bound to A "Poor" Carbapenem Substrate, Doripenem". Antibiotics (Basel). 8, pii: E145.
Mesiano, S.A., Peters, G.A., Amini, P., Wilson, R.A., Tochtrop, G.P., van den Akker. F. (2019) "Progestin therapy to prevent preterm birth: History and effectiveness of current strategies and development of novel approaches". Placenta 79, 46-42.
Barnes, M.D., Kumar, V., Bethel, C.R., Moussa, S.H., O’Donnell, J., Rutter, J.D., Good, C.E., Hujer, K.M., Hujer, A.M., Marshall, S.H., Kreiswirth, B.N., Richter, S.S., Rather, P.N., Jacobs, M.R., Papp-Wallace, K.M., van den Akker, F.*, Bonomo, R.A.* (2019) "Targeting Multidrug-Resistant Acinetobacter spp.: Sulbactam and the Diazabicyclooctenone β-Lactamase Inhibitor ETX2514 as a Novel Therapeutic Agent". mBio, e00159-19. *co-corresponding authors
Stomberski, C.T., Zhou, H.-L., Wang, L., van den Akker, F., Stamler, J.S. (2018) "Molecular recognition of S-nitrosothiol substrate by its cognate protein denitrosylase". J. Biol. Chem. 294, 1568-1578.
Vijayaraghavan, J., Kumar, V., Krishnan, N.P., Kaufhold, R.T., Zeng, X., Lin, J., van den Akker, F.
“ Structural studies and molecular dynamics simulations suggest a processive mechanism of exolytic lytic transglycosylase from Campylobacter jejuni. ”
Plos One 2018, e0197136.
Papp-Wallace, K.M.*, Nguyen, N.Q., Jacobs, M.R., Bethel, C.R., Barnes, M.D., Kumar, V., Bajaksouzian, S., Rudin, S.D., Bhavsar, S., Ravikumar, T., Deshpande, P.K., Patil, V., Yeole, R., Bhagwat, S.S., Patel, M.V., van den Akker, F.*, Bonomo, R.A.*
“ Strategic approaches to overcome resistance against Gram negative pathogens using beta-lactamase inhibitors and beta-lactam enhancers: The activity of three novel diazabicyclooctanes, zidebactam (WCK 5107), WCK 5153, WCK 4234. ”
J. Med. Chem 2018, 61, 4067-4086.
van den Akker, F.*, Bonomo, R.A.
“ Exploring additional dimensions of complexity in inhibitor design for serine beta-lactamases: mechanistic and intra- and inter-moleculra chemistry approach. ”
Front Microbiol. 2018, 9, 622.
Chen A., Tiosano, D., Guran, T., Baris, H.N., Bayram, Y., Mory, A., Shapiro-Kulnane, L., Hodges, C.A., Coban Akdemir, Z., Turan, S., Jhangiani, S.N., van den Akker, F., Hoppel, C.L., Salz, H.K., Lupski, J.R., Buchner, D.A.
“ Mutations in the mitochondrial ribosomal protein MRPS22 lead to primary ovarian insufficiency. ”
Hum Mol. Genet. 2018, 27, 1913-1926.
Nguyen N.Q., Krishnan N.P., Rojas L.J., Prati F., Caselli E., Romagnoli C., Bonomo R.A., van den Akker F.
“ Crystal structures of KPC-2 and SHV-1 beta-lactamases in complex with the boronic acid transition state analog S02030. ”
Antimicrob Agents Chemother. 2016, 60, 1760-6.
Krishnan N.P., Nguyen N.Q., Papp-Wallace K.M., Bonomo R.A., van den Akker F.
“ Inhibition of Klebsiella beta-Lactamases (SHV-1 and KPC-2) by Avibactam: A Structural Study. ”
Plos One Sep 4;10(9):e0136813 (2015)
Rodkey E.A., Winkler, M.L., Bethel C.R., Pagadala, S.R.R., Buynak, J.D., Bonomo R.A., van den Akker F.
“Penam sulfones and beta-lactamase inhibition: SA2-13 and the importance of the C2 side chain length and composition. ”
Plos One Jan 16;9(1):e85892 (2014)
Rodkey E.A., McLeod D.C., Bethel C.R., Smith K.M., Xu Y., Chai W., Che T., Carey P.R., Bonomo R.A., van den Akker F., Buynak J.D.
“beta-Lactamase Inhibition by 7-Alkylidenecephalosporin Sulfones: Allylic Transposition and Formation of an Unprecedented Stabilized Acyl-Enzyme. ”
J. Am. Chem. Soc. Epub Dec 3(2013)
von Wantoch Rekowski M., Kumar V., Zhou Z., Moschner J., Marazioti A., Bantzi M., Spyroulias G.A., van den Akker F., Giannis A., Papapetropoulos A.
“Insights into Soluble Guanylyl Cyclase Activation Derived from Improved Heme-Mimetics. ”
J. Med. Chem. Epub Oct 24(2013)
Kumar V., Martin F.E., Hahn M.G., Schaefer M., Stamler J.S., Stasch J.P., van den Akker F.
“Insights into BAY 60-2770 activation and S-nitrosylation-dependent desensitization of soluble guanylyl cyclase via crystal structures of homologous Nostoc H-NOX domain complexes. ”
Biochemistry Epub Apr 24 (2013)
Ke W., Pattanaik P., Bethel C.R., Sheri A., Buynak J.D., Bonomo R.A., van den Akker F.
“Structures of SHV-1 beta-lactamase with penem and penam sulfone inhibitors that form cyclic intermediates stabilized by carbonyl conjugation.”
Plos One e49035 (2012)
Rodkey E.A., Drawz S.M., Sampson J.M. Bethel C.R., Bonomo R.A., and van den Akker F.
“Crystal structure of a pre-acylation complex of the beta-lactamase inhibitor, sulbactam, bound to a sulfenamide bond containing thiol-beta-lactamase ”
J. Am. Chem. Soc. epub Sep 26, (2012)
Ke W., Laurent A.H., Armstrong M.D., Chen Y., Smith W.E., Liang J., Wright C.M., Ostermeier M., and van den Akker, F. “Structure of an Engineered beta-Lactamase Maltose Binding Protein Fusion Protein: Insights into Heterotropic Allosteric Regulation ”
Plos One 7: e39168 (2012)
Ke W, Rodkey R.A., Sampson J.M., Skalweit M.J., Sheri A., Pagadala S.R.R., Nottingham M.D., Buynak J.D., Bonomo R.A., van den Akker F.
“The importance of the trans-enamine intermediate as a beta-lactamase inhibition strategy probed in inhibitor-resistant SHV beta-lactamase variants”
ChemMedChem 7: 1002-1008 (2012)
Ke W., Bethel C.R., Papp-Wallace K.M., Pagadala S.R., Nottingham M., Fernandez D., Buynak J.D., Bonomo R.A., van den Akker F.
“Crystal structures of KPC-2 beta-lactamase in complex with 3-NPBA and PSR-3-226”
Antimicrob Agents Chemother ePub Feb 13 (2012)
Sampson J. M., Ke, W., Bethel, C. R., Pagadala, S. R. R., Nottingham, M. D., Bonomo R. A., Buynak, J. D., and van den Akker F.
“Ligand dependent disorder of the omega loop observed in extended-spectrum SHV-type beta-lactamases”
Antimicrob Agents Chemother 55 (1): 2303-2309 (2011).
Ke W., Sampson J. M., Ori C., Prati F., Drawz S. M., Bethel C. R., Bonomo R. A., and van den Akker F.
“Novel insights into the mode of inhibition of class A SHV-1 beta-lactamases revealed by boronic acid transition state inhibitors”
Antimicrob Agents Chemother 55 (1): 174-83 (2011).
Ma X., Beuve A., and van den Akker F.
“Crystal structure of the signaling helix coiled-coil domain of the beta1 subunit of the soluble guanylyl cyclase”
BMC Struct Biol 10: 2 (2010).
Martin F., Baskaran P., Ma X., Dunten P. W., Schaefer M., Stasch J. P., Beuve A., and van den Akker F.
“Structure of cinaciguat (BAY 58-2667) bound to Nostoc H-NOX domain reveals insights into heme-mimetic activation of the soluble guanylyl cyclase”
J Biol Chem 285 (29): 22651-7 (2010).
Ma X., Sayed N., Baskaran P., Beuve A., and van den Akker F.
“PAS-mediated dimerization of soluble guanylyl cyclase revealed by signal transduction histidine kinase domain crystal structure”
J Biol Chem 283 (2): 1167-78 (2008).
Ma X., Sayed N., Beuve A., and van den Akker F.
“NO and CO differentially activate soluble guanylyl cyclase via a heme pivot-bend mechanism”
EMBO J 26 (2): 578-88 (2007).
Sayed N., Baskaran P., Ma X., van den Akker F., and Beuve A.
“Desensitization of soluble guanylyl cyclase, the NO receptor, by S-nitrosylation”
Proc Natl Acad Sci U S A 104 (30): 12312-7 (2007).

Education

PhD

University of Washington

Post Doc

Lerner Research Institute, Cleveland Clinic