Marco Pires
Professor and Director of Graduate Studies
University of Virginia
Talk Information
Strategies for Membrane Permeability or Oral Bioavailability
16 June 2025, 09:20am - 09:35am, in the Pacific Jewel Ballroom
L05 – Systematic Determination of the Impact of Structural Edits on Accumulation into Mycobacteria
Professor Marcos M. Pires serves as a Professor of Chemistry and Director of Graduate Studies at the University of Virginia. He also holds a joint appointment in the Department of Microbiology, Immunology, and Cancer Biology at the UVA Cancer Center. His research focuses on chemical microbiology and immunology, particularly the development of synthetic tools to study bacterial cell walls and the creation of novel immunotherapeutic strategies against bacterial pathogens.
Academic Background
Dr. Pires earned his B.S. in Chemistry from Ithaca College in 2003 and completed his Ph.D. in Chemistry at Purdue University in 2009. He then pursued postdoctoral research as an NIH Fellow at the University of Pennsylvania from 2009 to 2011. Prior to joining the University of Virginia, he was a faculty member at Lehigh University.
Research Focus
Professor Pires's laboratory employs synthetic chemistry to construct analogs of bacterial cell wall components, enabling the study of peptidoglycan biosynthesis and remodeling in live bacteria. His team develops high-throughput screening platforms to measure the accumulation of small molecules in bacteria, aiming to inform the design of next-generation antibiotics that can overcome resistance mechanisms. Additionally, the lab explores chemical immunology approaches to modulate the immune response for targeted antimicrobial therapies.
Notable Contributions
Dr. Pires has significantly advanced the understanding of bacterial cell wall architecture and its role in pathogenesis. His work has led to the development of synthetic cell wall mimics that reveal how bacterial building blocks regulate surface remodeling and biosynthesis. Furthermore, his research into the molecular rules governing antibiotic accumulation in bacteria has provided valuable insights for the development of more effective antimicrobial agents.
Professional Engagements
Beyond his research, Professor Pires is actively involved in graduate education and mentorship at the University of Virginia. As Director of Graduate Studies in the Department of Chemistry, he oversees the academic progress of graduate students and contributes to curriculum development. He is also engaged in interdisciplinary collaborations within the UVA Cancer Center, reflecting his commitment to translating chemical biology research into therapeutic applications.
Through his innovative research and dedication to education, Professor Marcos M. Pires continues to make significant contributions to the fields of chemical biology and microbiology.
Structural Features That Drive Accumulation of Peptidic Antibiotics in Mycobacteria
Department of Chemistry, University of Virginia, Charlottesville, Virginia, USA
Most antibiotics currently used in the treatment of tuberculosis, such as isoniazid, rifampicin, ethambutol, and pyrazinamide, are small, hydrophobic molecules that were developed several decades ago. These molecular features of efficacious TB antibiotics have been purported to be a direct consequence of the difficult-to-cross mycomembrane barrier. The overuse of these therapeutics, compounded by suboptimal patient adherence due to the prolonged treatment regimens, has led to the emergence of multi-drug resistant, (MDR) and total drug-resistant (XDR) strains of Mtb.
There are notable exceptions, (e.g., rifampicin) to the size constraint purported to operate in TB antibiotics. Peptidic molecules that are well beyond Lipinski's Rule of Five (bRo5) have attracted interest in drug design because of their ability to bind targets with greater specificity and affinity. Broadly, peptide drugs have drawn considerable interest across disease areas including oncology and metabolic disorders. A noteworthy antibacterial example is the development of an entirely new class of macrocyclic peptide antibiotics (Zosurabalpin developed by Roche) that specifically target the lipopolysaccharide transporter in carbapenem-resistant Acinetobacter baumannii. Peptidic candidates are also emerging on the mycobacterial side. This growth in interest is highlighted by the recent discovery of evybactin and cyclomarin A, which was also the basis of the promising series of BacPROTACs.
Deciphering the principles that govern molecular accumulation in mycobacteria is central for achieving high antimycobacterial efficacy. A comprehensive understanding of how structure drives accumulation will enable the identification of high-potential drug candidates and the strategic redesign of existing chemical scaffolds to enhance their accumulation within mycobacterial cells. A prior challenge in the field was the general lack of tools to readily measure the arrival of molecules past the mycomembrane, which we addressed with the development of the Peptidoglycan Accessibility Click-Mediated Assessment (PAC-MAN) assay for live-cell analysis.
Herein, we systematically evaluated two structural alterations that could potentially enhance molecular accumulation past the mycomembrane: backbone N-methylation and macrocyclization. Through a comprehensive series of peptides, we demonstrated that specific structural features significantly influence accumulation levels in mycobacteria. This discovery lays the groundwork for a set of prescriptive modifications that can be employed in developing more effective antibiotics targeting Mycobacteria. By applying these strategies to a poorly permeable antibiotic, we observed that, in certain cases, these structural modifications can substantially enhance antibiotic activity against Mycobacteria.