Isaac Paddy

All Publications

• A cofactor-promiscuous HMGR from the Lyme disease pathogen illuminates diversity in bacterial isoprenoid biosynthesis. bioRxiv : the preprint server for biology Paddy, I. A., McCausland, J., Frazier, M., Chatterjee, P., Setegne, M., Eidam, O., Jacobs-Wagner, C., Dassama, L. M. 2026

  Abstract

  The Lyme disease pathogen Borrelia burgdorferi contains a highly reduced genome lacking many primary metabolic pathways. However, B. burgdorferi retains the mevalonate pathway that synthesizes isopentenyl pyrophosphate (IPP), the precursor to the peptidoglycan carrier lipid. While the mevalonate pathway and the enzyme that catalyzes its rate-limiting step (3-hydroxy-3-methyl glutaryl coenzyme A reductase, HMGR) are well studied in vertebrates, little is known about the pathway in B. burgdorferi and many pathogenic bacteria. In this work, we reveal that HMGR is a critical metabolic enzyme in B. burgdorferi. We demonstrate that loss of HMGR causes morphological defects and muted de novo synthesis of peptidoglycan; these defects are ameliorated by exogenous mevalonate and IPP. Biochemical characterization unveiled the HMGR as a highly unusual cofactor-promiscuous oxidoreductase that functions with both nicotinamide cofactors. Bioinformatics and biochemical characterization uncovered examples of similarly promiscuous HMGRs and revealed a previously unrecognized evolutionary link to cofactor choice. Moreover, structures of the enzyme reveal a highly divergent active site architecture. Together, these findings firmly establish HMGR as an opportunity target for the development of antibacterials for a diderm pathogen while highlighting cofactor promiscuity as an evolutionary acquired feature in HMGRs.

  View details for DOI 10.64898/2026.07.06.735745

  View details for PubMedID 42465499

  View details for PubMedCentralID PMC13370337

• A lipid compendium of a metabolically compromised bacterium provides insights into lipid acquisition, biosynthesis, and metabolism. bioRxiv : the preprint server for biology Chatterjee, P., Shin, H. E., Tuncel, M. I., Paddy, I. A., Lee, A. K., McCausland, J., Welander, P. V., Jacobs-Wagner, C., Dassama, L. M. 2026

  Abstract

  The Lyme disease agent Borrelia burgdorferi belongs to a class of metabolically compromised bacteria that cannot survive without host-derived lipids. Survival of the agent in tick and vertebrate hosts requires substantial nutrient acquisition and potential cell envelope remodeling. While prior studies identified cholesterol, cholesterol glycolipids, and phosphatidylcholines as membrane lipids in B. burgdorferi, the identity of many other membrane lipids, their origin, and their physiological relevance remain unknown. Here, we used a suite of untargeted and targeted high-resolution mass spectrometry methods to reveal a complex lipid profile of the pathogen and to identify the origin of its lipids. The analysis detected more than 500 lipids in B. burgdorferi, the majority of which are sourced from the environment. However, the bacterium selectively accumulates certain lipids while excluding others, suggesting discriminatory uptake. These include cholesteryl esters and triglycerides that are organized in foci within the pathogen. Intriguingly, the pathogen also synthesizes predominantly eukaryotic lipids such as the lysosomal bis(monoacylglycerol)phosphate and the plant glycolipid sulfoquinovosyl diacylglycerol (SQDG). The biosynthesis of the latter is carried out by enzymes that exhibit structural homology to plant oxidoreductases and galactosyltransferases, yet their closest orthologs are found in bacteria. This hints that the capability of SQDG synthesis is more widespread in spirochaetes and other bacteria. Together, the comprehensive lipid profiling we report here uncovers novel aspects of the physiology of the metabolically challenged B. burgdorferi and highlights lipid acquisition and synthesis pathways as potentially critical for pathogen survival.

  View details for DOI 10.64898/2026.05.22.727245

  View details for PubMedID 42239376

  View details for PubMedCentralID PMC13228262

• Isoprenoid biosynthesis is a metabolic vulnerability in the Lyme disease pathogen Borrelia burgdorferi Paddy, I. A. CELL PRESS. 2026: 51a

  View details for Web of Science ID 001717073300249

• Activation and Allostery in a Fungal SAMHD1 Hydrolase: An Evolutionary Blueprint for dNTP Catabolism JACS AU Pan, L., Lachowicz, J. C., Paddy, I., Xu, Y., Yang, Q., Zizola, C., Milne, A., Grove, T. L., Pandelia, M. 2025

  View details for DOI 10.1021/jacsau.5c00090

  View details for Web of Science ID 001469203800001

• Identifying Opportunity Targets in Gram-Negative Pathogens for Infectious Disease Mitigation. ACS central science Paddy, I. A., Dassama, L. M. 2025; 11 (1): 25-35

  Abstract

  Antimicrobial drug resistance (AMR) is a pressing global human health challenge. Humans face one of their grandest challenges as climate change expands the habitat of vectors that bear human pathogens, incidences of nosocomial infections rise, and new antibiotics discovery lags. AMR is a multifaceted problem that requires a multidisciplinary and an "all-hands-on-deck" approach. As chemical microbiologists, we are well positioned to understand the complexities of AMR while seeing opportunities for tackling the challenge. In this Outlook, we focus on vulnerabilities of human pathogens and posit that they represent "opportunity targets" for which few modulatory ligands exist. We center our attention on proteins in Gram-negative organisms, which are recalcitrant to many antibiotics because of their external membrane barrier. Our hope is to highlight such targets and explore their potential as "druggable" proteins for infectious disease mitigation. We posit that success in this endeavor will introduce new classes of antibiotics that might alleviate some of the current pressing AMR concerns.

  View details for DOI 10.1021/acscentsci.4c01437

  View details for PubMedID 39866699

  View details for PubMedCentralID PMC11758222

• The HD-Domain Metalloprotein Superfamily: An Apparent Common Protein Scaffold with Diverse Chemistries CATALYSTS Langton, M., Sun, S., Ueda, C., Markey, M., Chen, J., Paddy, I., Jiang, P., Chin, N., Milne, A., Pandelia, M. 2020; 10 (10)

  Abstract

  The histidine-aspartate (HD)-domain protein superfamily contains metalloproteins that share common structural features but catalyze vastly different reactions ranging from oxygenation to hydrolysis. This chemical diversion is afforded by (i) their ability to coordinate most biologically relevant transition metals in mono-, di-, and trinuclear configurations, (ii) sequence insertions or the addition of supernumerary ligands to their active sites, (iii) auxiliary substrate specificity residues vicinal to the catalytic site, (iv) additional protein domains that allosterically regulate their activities or have catalytic and sensory roles, and (v) their ability to work with protein partners. More than 500 structures of HD-domain proteins are available to date that lay out unique structural features which may be indicative of function. In this respect, we describe the three known classes of HD-domain proteins (hydrolases, oxygenases, and lyases) and identify their apparent traits with the aim to portray differences in the molecular details responsible for their functional divergence and reconcile existing notions that will help assign functions to yet-to-be characterized proteins. The present review collects data that exemplify how nature tinkers with the HD-domain scaffold to afford different chemistries and provides insight into the factors that can selectively modulate catalysis.

  View details for DOI 10.3390/catal10101191

  View details for Web of Science ID 000584225400001

  View details for PubMedID 34094591

  View details for PubMedCentralID PMC8177086