Antimicrobials through Chemoenzymatic Synthesis
Dr Alexander Kiefer
The Kiefer group is an interdisciplinary research team with focus on natural product-inspired drug development at the interface of organic synthesis and biocatalysis.
Our research and approach
Natural products (NPs) have historically played a crucial role in drug discovery due to their bioactivity-rich scaffolds, which serve as valuable templates for therapeutic agents. However, their use in drug development has dwindled, primarily because of the difficulties associated with isolating these compounds from natural sources or the limitations of conventional synthetic methods. By harnessing the unique reactivity and selectivity of enzymes from NP biosynthetic pathways combined with cutting-edge organic chemistry techniques, we aim to develop practical solutions to access those NPs and their analogs. Besides developing feasible synthetic routes for NPs active against Plasmodium falciparum, the causative pathogen of malaria, Mycobacterium tuberculosis and other microorganisms, we are focusing on the discovery of novel biocatalysts. By generating a biocatalyst library, we are aiming to fortify the traditional synthetic toolkit available for NP synthesis while providing deeper insights into underexplored enzyme chemistry.
Team members
Dr Alexander Kiefer
Group Leader
Publications
2025
Dipeptidic Phosphonates: Potent Inhibitors of Pseudomonas aeruginosa Elastase B Showing Efficacy in a Murine Keratitis Model
Kiefer A, Schütz C, Englisch C, Kolling D, Speicher S, Kany A, Shafiei R, Wadood N, Aljohmani A, Wirschem N, …, Haupenthal J, Hirsch A (2025)
Adv. Sci.DOI: 10.1002/advs.202411807
Unlocking the Antiviral Arsenal: Structure-Guided Optimization of Small-Molecule Inhibitors against RSV and hCoV-229E
Karhan C, Sake S, Gunesch A, Grethe C, Hellwinkel B, Köhler N, Kiefer A, Hapko U, Kany A, Pietschmann T, Hirsch A (2025)
European journal of medicinal chemistryDOI: 10.1016/j.ejmech.2025.117282
2024
The Natural Products Discovery Center: Release of the First 8490 Sequenced Strains for Exploring Actinobacteria Biosynthetic Diversity
Kalkreuter E, Kautsar S, Yang D, Bader C, Teijaro C, Fluegel L, Davis C, Simpson J, Lauterbach L, Steele A, …, Carvalho L, Shen B (2024)
bioRxivDOI: 10.1101/2023.12.14.571759
2023
The many facets of sulfur incorporation in natural product biosynthesis
Steele A, Kiefer A, Shen B (2023)
Current opinion in chemical biology 76DOI: 10.1016/j.cbpa.2023.102366
Application of a Biocatalytic Strategy for the Preparation of Tiancimycin-Based Antibody-Drug Conjugates Revealing Key Insights into Structure-Activity Relationships
Steele A, Kiefer A, Hwang D, Yang D, Teijaro C, Adhikari A, Rader C, Shen B (2023)
Journal of medicinal chemistry 66 (2): 1562-1573DOI: 10.1021/acs.jmedchem.2c01771
An Artificial In Vitro Metabolism to Angiopterlactone B Inspired by Traditional Retrosynthesis
Kiefer A, Liu Y, Gummerer R, Jäger C, Deska J (2023)
Angewandte Chemie (International ed. in English) 62 (23)DOI: 10.1002/anie.202301178
pH-Responsive Dynaplexes as Potent Apoptosis Inductors by Intracellular Delivery of Survivin siRNA
Liu Y, Ashmawy S, Latta L, Weiss A, Kiefer A, Nasr S, Loretz B, Hirsch A, Lee S, Lehr C (2023)
Biomacromolecules 24 (8): 3742-3754DOI: 10.1021/acs.biomac.3c00424
Insights into the biosynthesis of icumazole, unveiling a distinctive family of crotonyl-CoA carboxylase/reductase
Xie F, Kiefer A, Hirsch A, Kalinina O, Fu C, Müller R (2023)
Cell Reports Physical Science 4 (5)DOI: 10.1016/j.xcrp.2023.101394
2022
Phage display-based discovery of cyclic peptides against the broad spectrum bacterial anti-virulence target CsrA
Jakob V, Zoller B, Rinkes J, Wu Y, Kiefer A, Hust M, Polten S, White A, Harvey P, Durek T, …, Kazmaier U, Empting M (2022)
European journal of medicinal chemistry 231DOI: 10.1016/j.ejmech.2022.114148
Structure-Guided Optimization of Small-Molecule Folate Uptake Inhibitors Targeting the Energy-Coupling Factor Transporters
Kiefer A, Bousis S, Hamed M, Diamanti E, Haupenthal J, Hirsch A (2022)
J. Med. Chem.DOI: 10.1021/acs.jmedchem.1c02114
Sandacrabins - Structurally Unique Antiviral RNA Polymerase Inhibitors from a Rare Myxobacterium
Bader C, Panter F, Garcia R, Tchesnokov E, Haid S, Walt C, Spröer C, Kiefer A, Götte M, Overmann J, Pietschmann T, Müller R (2022)
Chem. Eur. J. 28 (10)DOI: 10.1002/chem.202104484
Inhibitors of Pseudomonas aeruginosa virulence factor LasB
Ducho C, Hartmann R, Haupenthal J, Hirsch A, Kany A, Kaya C, Konstantinovic J, Voos K, Walter I, Yahiaoui S, …, Jumde R, Kiefer A (2022)
Patent A61K31/095; A61K31/10; A61K31/167; A61K31/4184; A61K31/426; A61K31/428; A61K31/4406; A61P31/04; C07C323/60; C07D213/74; C07D235/30; C07D277/46; C07D277/82; C07D333/36; C07F9/38; C07F9/40; (WO2022043322A1)
2020
Flexible Fragment Growing Boosts Potency of Quorum-Sensing Inhibitors against Pseudomonas aeruginosa Virulence
Zender M, Witzgall F, Kiefer A, Kirsch B, Maurer C, Kany A, Xu N, Schmelz S, Börger C, Blankenfeldt W, Empting M (2020)
ChemMedChem 15 (2): 188-194DOI: 10.1002/cmdc.201900621
2019
Syntheses of Cyclomarins – Interesting Marine Natural Products with Distinct Mode of Action towards Malaria and Tuberculosis
Kiefer A, Kazmaier U (2019)
Synthesis 51 (01): 107-121DOI: 10.1055/s-0037-1610377
Synthesis of New Cyclomarin Derivatives and Their Biological Evaluation towards Mycobacterium Tuberculosis and Plasmodium Falciparum
Kiefer A, Bader C, Held J, Esser A, Rybniker J, Empting M, Müller R, Kazmaier U (2019)
Chem. Eur. J. 25 (37): 8894-8902DOI: 10.1002/chem.201901640
2018
Synthesis of modified β-methoxyphenylalanines via diazonium chemistry and their incorporation in desoxycyclomarin analogues
Kiefer A, Kazmaier U (2018)
Org. Biomol. Chem. 17 (1): 88-102DOI: 10.1039/C8OB02777C
2015
Palladium‐Catalyzed Allylic Alkylation Reactions of Glycolates as a Tool for the Synthesis of Functionalized α‐Hydroxy Esters
Kiefer A, Gawas D, Kazmaier U (2015)
Liebigs Ann. 2015 (26): 5810-5816DOI: 10.1002/ejoc.201500755