@article{nie_valdes-pena_frohock_smits_daiker_gilbertie_v. schnabel_pierce_2024, title={Expanded library of novel 2,3-pyrrolidinedione analogues exhibit anti-biofilm activity}, volume={99}, ISSN={["1464-3405"]}, url={https://doi.org/10.1016/j.bmcl.2024.129609}, DOI={10.1016/j.bmcl.2024.129609}, abstractNote={Herein we report a new library of 2,3-pyrrolidinedione analogues that expands on our previous report on the antimicrobial studies of this heterocyclic scaffold. The novel 2,3-pyrrolidinediones reported herein have been evaluated against S. aureus and methicillin-resistant S. aureus (MRSA) biofilms, and this work constitutes our first report on the antibiofilm properties of this class of compounds. The antibiofilm activity of these 2,3-pyrrolidinediones has been assessed through minimum biofilm eradication concentration (MBEC) and minimum biofilm inhibition concentration (MBIC) assays. The compounds displayed antibiofilm properties and represent intriguing scaffolds for further optimization and development.}, journal={BIOORGANIC & MEDICINAL CHEMISTRY LETTERS}, author={Nie, Minhua and Valdes-Pena, M. Alejandro and Frohock, Bram H. and Smits, Emma and Daiker, Jennifer C. and Gilbertie, Jessica M. and V. Schnabel, Lauren and Pierce, Joshua G.}, year={2024}, month={Feb} }
 @article{breunig_valdes-pena_ratchford_pierce_2024, title={Total Synthesis and Microbiological Evaluation of Leopolic Acid A and Analogues}, volume={1}, ISSN={["2694-2437"]}, url={https://doi.org/10.1021/acsbiomedchemau.3c00068}, DOI={10.1021/acsbiomedchemau.3c00068}, abstractNote={New antimicrobial scaffolds are scarce, and there is a great need for the development of novel therapeutics. In this study, we report a convergent 9-step synthesis of leopolic acid A and a series of targeted analogues. The designed compounds allowed for incorporation of non-natural ureido dipeptide moieties and 4- and 5-position substituents around the 2,3-pyrrolidinedione of leopolic acid A. Leopolic acid A displayed modest antimicrobial activity (32 μg/mL) against MRSA, while the most active analogues displayed slightly improved activity (8–16 μg/mL). Additionally, several of the leopolic acid A analogues displayed promising antibiofilm activity, most notably having an MBEC:MIC ratio of ∼1. Overall, this work represents an initial SAR of the natural product and a framework for further optimization of these bioactive scaffolds within the context of bioactive pyrrolidinediones.}, journal={ACS BIO & MED CHEM AU}, author={Breunig, Jamie L. and Valdes-Pena, M. Alejandro and Ratchford, Andrew W. and Pierce, Joshua G.}, year={2024}, month={Jan} }
 @misc{valdes-pena_massaro_lin_pierce_2021, title={Leveraging Marine Natural Products as a Platform to Tackle Bacterial Resistance and Persistence}, volume={54}, ISSN={["1520-4898"]}, url={https://doi.org/10.1021/acs.accounts.1c00007}, DOI={10.1021/acs.accounts.1c00007}, abstractNote={ConspectusAntimicrobial resistance to existing antibiotics represents one of the greatest threats to human health and is growing at an alarming rate. To further complicate treatment of bacterial infections, many chronic infections are the result of bacterial biofilms that are tolerant to treatment with antibiotics because of the presence of metabolically dormant persister cell populations. Together these threats are creating an increasing burden on the healthcare system, and a "preantibiotic" age is on the horizon if significant action is not taken by the scientific and medical communities. While the golden era of antibiotic discovery (1940s-1960s) produced most of the antibiotic classes in clinical use today, followed by several decades of limited development, there has been a resurgence in antibiotic drug discovery in recent years fueled by the academic and biotech sectors. Historically, great success has been achieved by developing next-generation variants of existing classes of antibiotics, but there remains a dire need for the identification of novel scaffolds and/or antimicrobial targets to drive future efforts to overcome resistance and tolerance. In this regard, there has been no more valuable source for the identification of antibiotics than natural products, with 69-77% of approved antibiotics either being such compounds or being derived from them.Our group has developed a program centered on the chemical synthesis and chemical microbiology of marine natural products with unusual structures and promising levels of activity against multidrug-resistant (MDR) bacterial pathogens. As we are motivated by preparing and studying the biological effects of these molecules, we are not initially pursuing a biological question but instead are allowing the observed phenotypes and activities to guide the ultimate project direction. In this Account, our recent efforts on the synoxazolidinone, lipoxazolidinone, and batzelladine natural products will be discussed and placed in the context of the field's greatest challenges and opportunities. Specifically, the synoxazolidinone family of 4-oxazolidinone-containing natural products has led to the development of several chemical methods to prepare antimicrobial scaffolds and has revealed compounds with potent activity as adjuvants to treat bacterial biofilms. Bearing the same 4-oxazolidinone core, the lipoxazolidinones have proven to be potent single-agent antibiotics. Finally, our synthetic efforts toward the batzelladines revealed analogues with activity against a number of MDR pathogens, highlighted by non-natural stereochemical isomers with superior activity and simplified synthetic access. Taken together, these studies provide several distinct platforms for the development of novel therapeutics that can add to our arsenal of scaffolds for preclinical development and can provide insight into the biochemical processes and pathways that can be targeted by small molecules in the fight against antimicrobial-resistant and -tolerant infections. We hope that this work will serve as inspiration for increased efforts by the scientific community to leverage synthetic chemistry and chemical microbiology toward novel antibiotics that can combat the growing crisis of MDR and tolerant bacterial infections.}, number={8}, journal={ACCOUNTS OF CHEMICAL RESEARCH}, publisher={American Chemical Society (ACS)}, author={Valdes-Pena, M. Alejandro and Massaro, Nicholas P. and Lin, You-Chen and Pierce, Joshua G.}, year={2021}, month={Apr}, pages={1866–1877} }