The overall goal of our research is to understand the mechanisms bacteria use to resist antimicrobials and the host immune system to ultimately guide future therapeutic advances. Bacterial resistance to antibiotics is growing rapidly while no new therapeutics are being introduced to the clinic. This is a major threat to human health as we are reliant on effective antibiotics for many of the modern medical advances which have increased our lifespan. Multi-drug resistant Klebsiella pneumoniae is categorized as “Priority 1: Critical” on the World Health Organization priority pathogens list for R&D of new antibiotics. In addition to being resistant to antibiotics, hypervirulent K. pneumoniae has a robust extracellular polysaccharide capsule that allows it to evade clearance by the host immune system and the spread within the community of healthy individuals.
The current focus of the lab is understanding the interactions of antimicrobial peptides with extracellular polysaccharides produced by K. pneumoniae. We are continuing to investigate 1) the mechanism we discovered that antimicrobial peptides use to disrupt the capsule layer of K. pneumoniae and 2) the role that polysaccharides play in the susceptibility of hypermucoviscous biofilms to disruption by polyproline peptides. In addition to the work with polysaccharide interactions, we are investigating the potential of host directed therapy to better treat K. pneumoniae lung infections. For more information about the research in the Fleeman lab visit our lab webpage:
Renee Fleeman, Travis M. LaVoi, Radleigh G. Santos, Angela Morales, Adel Nefzi, Gregory S. Welmaker, José L. Medina-Franco, Marc A. Giulianotti, Richard A. Houghten, and Lindsey N. Shaw.The Development of Novel
- Anti-Resistance Agents Targeting the Efflux Pumps of Multi-Drug Resistant Bacterial Pathogens. Frontiers in Microbiology. June 14, 2018. DOI 10.3389/fmicb.2018.01301.
- Renee Fleeman, Kurt S. Van Horn, Megan M. Barber, Whittney N. Burda, Roman Manetsch, and Lindsey N. Shaw. Characterizing the Antimicrobial Activity of N2,N4-Disubstituted Quinazoline-2,4-Diamines Towards Multidrug Resistant Acinetobacter baumannii. Antimicrob. Agents Chemother. March 13, 2017.DOI 10.1021/jm501628s.
- Kirkpatrick, Christine, Broberg, Christopher, McCool, Elijah, Lee, Woo Jean, Chao, Alex, McConnell, Evan, Pritchard, David, Hebert, Michael, Fleeman, Renee, Adams, Jessie, Jamil, Amer, Madera, Laurence, Strömstedt, Adam, Goransson, Ulf, Liu, Yufeng, Hoskin, David, Shaw, Lindsey, Hicks, Leslie.”The ‘PRISMS’ pipeline for natural product bioactive peptide discovery”. Analytical Chemistry. January 17, 2017. DOI: 10.1021/acs.analchem.6b03625.
- Andy Wiess, Renee M. Fleeman, Lindsey N. Shaw. Exposing the Unique Connection between Metabolism and Virulence in Staphylococcus aureus. Cell Chemical Biology. November 17, 2016. DOI: 10.1016/j.chembiol.2016.11.003.
- Yangmei Li, Nina Bionda, Renee Fleeman, Hongjie Wang, Akihiko Ozawa, Richard A. Houghten, Lindsey Shaw. Identification of 5,6-dihydroimidazo[2,1-b] thiazoles as a New Class of Antimicrobial Agents. Bioorganic and medicinal chemistry. November 1, 2016. DOI: 10.1016/j.bmc.2016.09.027.
- Jacqueline L. von Salm, Christopher G. Witowski, Renee M. Fleeman, James B. McClintock, Charles D. Amsler, Lindsey N. Shaw, and Bill J. Baker. Darwinolide, a New Diterpene Scaffold That Inhibits Methicillin-Resistant Staphylococcus aureus Biofilm from the Antarctic Sponge Dendrilla membranosa. Organic Letters. June 3, 2016. Featured as ACS Editor’s Choice June 30th 2016; 90,000+ views in 2016; most viewed article from ACS. DOI: 10.1021/acs.orglett.6b00979.
- Nina Bionda,Renee M. Fleeman, César de la Fuente-Núñez,Maria C. Rodriguez, Fany Reffuveille, Lindsey N. Shaw, Irena Pastar, Stephen C. Davis, Robert E. W. Hancock,and Predrag Cudic. Identification of novel cyclic lipopeptides from a positional scanning combinatorial library with enhanced antibacterial and antibiofilm activites. Eur J Med Chem. January 27, 2016. DOI: 10.1016/j.ejmech.2015.11.032.
- Renee Fleeman, Travis M. LaVoi, Radleigh G. Santos, Angela Morales, Adel Nefzi, Gregory S. Welmaker, José L. Medina-Franco, Marc A. Giulianotti, Richard A. Houghten, and Lindsey N. Shaw.Combinatorial Libraries as a Tool for the Discovery of Novel, Broad-Spectrum Antibacterial Agents Targeting the ESKAPE Pathogens. J. Med. Chem. April 23, 2015. DOI: 10.1021/jm501628s.
- Van Horn K, Burda W, Fleeman RM, Manetsch R, Shaw L. Antibacterial Activity of a Series of N2,N4-Disubstituted Quinazoline-2,4-Diamines. JMedChem. April 10, 2014. DOI: 10.1021/jm500039e.
- Bionda N, Fleeman RM, Shaw LN, Cudic P. Effect of Ester to Amide or N-methyl Amide Substitution on Membrane Depolarization and Antibacterial Activity of Novel Cyclic Lipopeptides. ChemMedChem. August 8, 2013. DOI: 10.1002/cmdc.201300173.
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