About

Andrzej Joachimiak is a Professor of Biochemistry and Molecular Biophysics at The University of Chicago. His research focuses on the structural genomics of bacterial drug targets, utilizing high-throughput pipelines to determine protein structures from pathogenic and related bacteria. His work has contributed to the understanding of various bacterial proteins, including those involved in antibiotic resistance and pathogenicity. Joachimiak's research also encompasses the structural system biology of proteins from organisms such as Clostridioides difficile and Klebsiella pneumoniae, as well as studies on enzyme mechanisms and immune responses related to SARS-CoV-2. His contributions advance the molecular understanding of bacterial functions and aid in the development of therapeutic strategies.

Research topics

• Biology
• Virology
• Biochemistry
• Medicine
• Chemistry
• Computational biology
• Computer Science
• Immunology
• Biophysics
• Crystallography

Selected publications

• Macromolecular Crystallography at the Upgraded Advanced Photon Source

  Synchrotron Radiation News · 2026-03-04

  articleOpen access
  PublisherDOI

• Phylogenetic Analysis and Structural Evaluation of <i>Staphylococcus aureus</i> Serine-Aspartate Repeat-Containing Protein D with a Focus on Periprosthetic Joint Infection

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-05

  articleOpen access1st author

  ABSTRACT Serine–aspartate repeat-containing protein D (SdrD) is a Staphylococcus aureus cell wall–anchored, calcium-binding adhesin member of the MSCRAMM Sdr subfamily that may contribute to bacterial adhesion and virulence. S. aureus is the most common cause of periprosthetic joint infection (PJI). Population-level distribution and sequence diversity of SdrD among clinical PJI isolates have not been systematically characterized, and the SdrD binding mechanism is still not well understood. To address these gaps, sdrD alleles were queried across 156 newly sequenced PJI isolates and compared to publicly available S. aureus genomes, and nucleotide– and protein-level phylogenies of the sdrCDE locus constructed. The SdrD crystal structure from S. aureus JH1 was determined, with solution small-angle X-ray scattering (SAXS) and molecular dynamics (MD) simulations, and assessment of conformational changes with calcium depletion. Three dominant sdrD subtypes were defined, associating with USA300, JH1, and TCH60; the JH1 sdrD subtype was predominant among PJI isolates. Structural studies showed that the conformation of individual domains and interdomain organization of the multidomain SdrD have limited flexibility in solution, and that the calcium-binding B domain retains its core fold under conditions of calcium depletion. Together, the findings presented support functional diversification among Sdr family members in mediating host attachment and inform a re-evaluation of the ligand-binding mechanism previously proposed for SdrD. AUTHOR SUMMARY Staphylococcus aureus is the leading cause of infections that develop around joint implants (periprosthetic joint infection, PJI). This bacterium has a large arsenal of surface proteins that allow it to stick to human tissues and implanted devices. This work focused on one such protein, SdrD, which has been linked to implant-associated infections but the structure and diversity of which among patients with PJI had not been well characterized. The genetic sequences of SdrD were analyzed across thousands of bacterial genomes, including those from patients with PJI. Distinct genetic variants of the protein were found, one of which was particularly common with PJI. The three-dimensional structure of SdrD was determined at atomic resolution and solution small-angle X-ray scattering (SAXS) and molecular dynamics used to study how it moves and responds to changes in its environment. Contrary to what was previously described, SdrD was shown to be relatively rigid. These findings change how SdrD’s mechanism of action should be considered, potentially informing design strategies to block bacterial attachment before infection takes hold.

  PublisherDOI

• N-terminal domain swapping: A new paradigm for spermidine/spermine N-acetyltransferase (SSAT) protein structures?

  Biochemical and Biophysical Research Communications · 2025-01-10 · 1 citations

  articleOpen access

  Enterococcus faecalis is a multi-drug-resistant human pathogen that is found in a variety of environments and is challenging to treat. Under stress conditions, some bacteria regulate intracellular polyamine concentrations via polyamine acetyltransferases to reduce their toxicity. The E. faecalis genome encodes two polyamine acetyltransferases: PmvE and BltD. Both of these proteins belong to the Gcn5-related N-acetyltransferase (GNAT) superfamily. It is unclear why there are two enzymes with similar substrate specificities in this organism. To better understand the structure/function relationship of the E. faecalis BltD enzyme, we determined its crystal structure and performed additional assays to explore its oligomeric state and enzymatic activity. The goal was to determine whether there were structural or catalytic differences between this enzyme and other polyamine acetyltransferases that could explain this redundancy and be exploited for future development of targeted inhibitors for this important human pathogen. We found the BltD enzyme was structurally unique due to its N-terminal domain swapped dimer. However, this enzyme adopts a catalytically active monomer rather than dimer in solution. This indicates the crystal structure we obtained may represent a state that forms at high protein and salt concentrations and at low pH used during crystallization. The BltD dimer found in the crystal may represent a unique view of how an inhibitory peptide or molecule could be designed to occupy its active site. Additionally, this structure shows the extensive flexibility of the N-terminal portion of the E. faecalis BltD enzyme.

  PublisherDOI

• Crystal Structure of N-Acetyl Transferase Domain-Containing Protein from Bacteroides fragilis

  2025-08-29

  datasetSenior author
  PublisherDOI

• Structural insights into the inhibition of <i>M. tuberculosis</i> Prolyl-tRNA synthetase by derivatives of 3-aminopyrazine-2-carboxamide

  Structural Dynamics · 2025-09-01

  articleOpen accessSenior author

  Tuberculosis (TB) is recognized as the second leading cause of death globally from a single infectious agent, following SARS-CoV-2 pneumonia. Aminoacyl-tRNA synthetases (aaRS) are essential enzymes responsible for attaching amino acids to their cognate tRNAs. These enzymes represent a promising set of targets for selective drug design due to the divergence between prokaryotic and eukaryotic aaRS. Recently, a new class of 3-aminopyrazine- 2-carboxamide derivatives has been identified as potent inhibitors of prolyl-tRNA synthetase (ProRS) from Mycobacterium tuberculosis (Mtb). These compounds exhibit significant antimycobacterial activity against Multi Drug Resistant strains of Mtb and demonstrate cytotoxicity against HepG2 human hepatocellular carcinoma cells. In this study, we present the crystal structures of MtbProRS in complex with five distinct 3-aminopyrazine-2-carboxamide derivatives. Structural analysis reveals that these inhibitors compete with ATP for the binding site of MtbProRS. Importantly, a critical hydrogen bond between the Glu144 of MtbProRS and the amino group of the carboxamide is identified, providing insights into the selective inhibition of MtbProRS over human ProRS.

  PublisherDOI

• Structural genomics of bacterial drug targets: Application of a high-throughput pipeline to solve 58 protein structures from pathogenic and related bacteria

  Microbiology Resource Announcements · 2025-05-20

  articleOpen access

  Antibiotic resistance remains a leading cause of severe infections worldwide. Small changes in protein sequence can impact antibiotic efficacy. Here, we report deposition of 58 X-ray crystal structures of bacterial proteins that are known targets for antibiotics, which expands knowledge of structural variation to support future antibiotic discovery or modifications.

  PublisherDOI

• Different chemical scaffolds bind to L-phe site in Mycobacterium tuberculosis Phe-tRNA synthetase

  European Journal of Medicinal Chemistry · 2025-01-31 · 1 citations

  articleOpen accessSenior authorCorresponding
  PublisherOA PDFDOI

• A funnel approach to enable analyses of epitope-specific human CD4 T cells specific for influenza and SARS-CoV-2

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-17

  preprintOpen access

  ABSTRACT Protection against pathogens relies heavily on the adaptive immune response, whose key regulators are CD4 T cells. CD4 T cells, notable for their complex repertoire and functional potential, can most easily be dissected by identifying, quantifying, characterizing, and isolating epitope-specific cells. In the study reported here, we present a systematic and unbiased strategy that has enabled the identification of highly immunogenic peptide epitopes derived from influenza virus and SARS-CoV-2, presented by human HLA-DR proteins. Coupling the use of HLA-DR transgenic mice with infection and vaccination and highly sensitive epitope-specific cytokine ELISpot assays, we have narrowed the potential epitopes from 450 to 600 peptides to 5–15 peptides for each allele by an iterative process of elimination and selection, which we have termed a funnel approach. These epitopes have been validated in HLA-DR-typed human CD4 T cells directly ex vivo and enabled the derivation and implementation of HLA-DR peptide tetramers. Tetramer staining of human PBMCs enriched for CD4 T memory populations from healthy adult subjects, highlighted this approach as a sensitive and specific method for identifying novel epitopes, and subsequent CD4 T-cell responses to human viral infections. IMPORTANCE Tracking single epitope-specific CD4 T cells enables sophisticated analyses of the human response to infectious pathogens, vaccines, and probing the human CD4 T-cell immune memory compartment. The studies presented here provide an unbiased strategy for accomplishing this goal and provide a verified compilation of candidate HLA-DR-restricted CD4 T-cell peptide epitopes for future studies by researchers in the field of human immunology.

  PublisherOA PDFDOI

• Crystal structure of T6SS effector-immunity complex PA3907-PA3908 from Pseudomonas aeruginosa

  2025-06-04

  dataset
  PublisherDOI

• The Ultrahigh-Resolution Protein Crystal Structure of Crambin

  Structural Dynamics · 2025-09-01

  articleOpen accessSenior author

  Ultra-high-resolution crystal structures of proteins provide critical insights into protein structure, dynamics, hydrogen bonding, and solvent networks. Crambin, a small hydrophobic storage protein consisting of 46 residues (4.7 kDa), is found in the embryonic tissue of seeds from Crambe abyssinica. This protein is renowned for its ability to crystallize readily, forming some of the best-ordered macromolecular crystals known, which diffract X-rays to the highest sub-atomic resolution recorded for any protein to date. We have previously reported the room temperature structure of crambin, refined to an exceptional resolution of 0.70 Å using SHELXL. That analysis revealed intricate details of the dynamic solvent network, characterized by alternative side chain conformations and shifts in water molecule positions. In this work, we extend our investigation by presenting new structural data collected at cryogenic temperatures: 15K using liquid helium and 100K using liquid nitrogen cooling. We will report the ultra-high-resolution structures at 15K and 100K, providing a comparative analysis of the solvent networks across these different temperature datasets. This comparison aims to deepen our understanding of the solvent and protein dynamics, offering valuable insights into the protein interactions within solvent environments. Our findings underscore the significance of ultrahigh-resolution crystallography in elucidating the complex interplay between proteins and their solvent environments, with potential implications for the broader field of structural biology.

  PublisherDOI

Recent grants

• NIH Grant U54GM074942

  NIH · $96.1M · 2011

• NIH Grant U54GM094585

  NIH · $67.4M · 2015

• NIH Grant P50GM062414

  NIH · $33.2M · 2005

• The Midwest Center for Structural Genomics - Community Resource

  NIH · $2.8M · 2015–2019

Frequent coauthors

• Youngchang Kim

  421 shared

• R. Jedrzejczak

  Argonne National Laboratory

  331 shared

• K. Michalska

  University of Chicago

  309 shared

• J. Osipiuk

  University of Chicago

  194 shared

• N. Maltseva

  University of Chicago

  177 shared

• Kemin Tan

  Argonne National Laboratory

  164 shared

• M. Endres

  Molecular Biology Consortium

  160 shared

• G. Babnigg

  Argonne National Laboratory

  158 shared

Labs

• Andrzej Joachimiak LabPI

  1-2 sentence research focus

Education

• Doctor of Sciences

  Institute of Biochemistry and Biophysics, Polish Academy of Sciences

  1993

• MS and PhD, Department of Mathematics, Physics and Chemistry

  Uniwersytet im Adama Mickiewicza w Poznaniu

  1979