The Pires lab uses synthetic chemistry as a platform to construct cell wall analogs that metabolically label live bacteria and mimic key aspects of cell wall architecture. Through this work, the interrogation of cell wall remodeling and processing in pathogenic bacteria will guide the design of next-generation antibiotics that circumvent resistance mechanisms. Moreover, we are working to establish the fundamental framework of a non-traditional antibiotic therapy based on the specific recruitment of components of the immune cells to target the destruction of pathogenic bacteria.

Every year in the United States, over two million people are afflicted with bacterial infections resistant to FDA-approved antibiotics. In order to counter the rapid rise in drug-resistance in bacteria, new drug targets and diagnostic tests are urgently needed. The bacterial cell wall has proven to be a rich source of antibiotic drug discovery. However, there are fundamental aspects of bacterial cell wall assembly and its interaction with the host organism that are yet to be fully elucidated.

Determination of Accumulation in Bacteria

Multidrug-resistant (MDR) bacterial infections are widely recognized as one of the most urgent global health threats due to their high resistance to nearly all available antibiotics. The rising prevalence of infections caused by this pathogen severely limits treatment options and poses a significant challenge to modern healthcare systems. The primary obstacle in treating infections (especially diderm bacteria) lies in the bacterium’s unique outer membrane, which acts as a formidable barrier, preventing many antibiotics from reaching their intracellular targets. Despite the critical need for new antibiotics and adjuvants that can overcome this barrier, our understanding of the molecular rules that govern antibiotic accumulation into bacteria remains limited. Our lab aims to address this gap by developing and applying innovative high-throughput screening platforms designed to measure the accumulation of small molecules with subcellular resolution.

Bacterial Cell Wall Probes – Chemical Microbiology

The Pires laboratory will leverage the laboratory expertise in building synthetic bacterial cell wall mimics to reveal key aspects of peptidoglycan recognition and cell wall remodeling. We anticipate that interrogation of cell wall remodeling and processing in pathogenic bacteria will guide the design of next-generation antibiotics that circumvent resistance mechanisms. Our work has yielded synthetic cell wall mimics that reveal how bacterial cell wall building blocks regulate surface remodeling and biosynthesis.

Synthetic Immunotherapeutics Against Bacterial Pathogens

We are developing unique antimicrobial therapeutic strategies based on a specific modulation of the immune response to combat bacterial infections. We have established novel methods to re-engage components of the immune system to induce a targeted immunological response to the site of infection. The goal is to assemble and evaluate agents that induce the recruitment of antibodies or the direct engagement with human immune cells. This new class of agents will constitute a way of mobilizing the immune system to target poorly immunogenic bacterial pathogens.

RECENT PUBLICATIONS

A Chemical Approach to Assess the Impact of Post-translational Modification on MHC Peptide Binding and Effector Cell Engagement. Kelly JJ, Bloodworth N, Shao Q, Shabanowitz J, Hunt D, Meiler J, Pires MM. ACS Chem Biol. 2024 Aug 16.

Identification of a family of peptidoglycan transpeptidases reveals that Clostridioides difficile requires noncanonical cross-links for viability. Bollinger KW, Müh U, Ocius KL, Apostolos AJ, Pires MM, Helm RF, Popham DL, Weiss DS, Ellermeier CD.Proc Natl Acad Sci U S A. 2024 Aug 20;121(34):e2408540121.

Selective Recruitment of Antibodies to Cancer Cells and Immune Cell-mediated Killing via In Situ Click Chemistry. Ankrom ET, Dalesandro B, Pires MM, Thévenin D.ChemMedChem. 2024 Aug 1:e202400356. doi: 10.1002/cmdc.202400356.

Share Targeted acidosis mediated delivery of antigenic MHC-binding peptides. Kelly JJ, Ankrom ET, Newkirk SE, Thévenin D, Pires MM.Front Immunol. 2024 Apr 11;15:1337973.

A modified BCG with depletion of enzymes associated with peptidoglycan amidation induces enhanced protection against tuberculosis in mice. Shaku MT, Um PK, Ocius KL, Apostolos AJ, Pires MM, Bishai WR, Kana BD.Elife. 2024 Apr 19;13:e89157.

Bioluminescence-Based Determination of Cytosolic Accumulation of Antibiotics in Escherichia coli. Dash R, Holsinger KA, Chordia MD, Gh MS, Pires MM.ACS Infect Dis. 2024 May 10;10(5):1602-1611.

Noninvasive Analysis of Peptidoglycan from Living Animals. Ocius KL, Kolli SH, Ahmad SS, Dressler JM, Chordia MD, Jutras BL, Rutkowski MR, Pires MM.Bioconjug Chem. 2024 Apr 17;35(4):489-498.

Neisseria gonorrhoeae scavenges host sialic acid for Siglec-mediated, complement-independent suppression of neutrophil activation. Cardenas AJ, Thomas KS, Broden MW, Ferraro NJ, Pires MM, John CM, Jarvis GA, Criss AK.mBio. 2024 May 8;15(5):e0011924.

Targeting Iron - Respiratory Reciprocity Promotes Bacterial Death. Sharifian Gh M, Norouzi F, Sorci M, Zaid TS, Pier GB, Achimovich A, Ongwae GM, Liang B, Ryan M, Lemke M, Belfort G, Gadjeva M, Gahlmann A, Pires MM, Venter H, Harris TE, Laurie GW.bioRxiv [Preprint]. 2024 Mar 1:2024.03.01.582947.

Measurement of Accumulation of Antibiotics to Staphylococcus aureus in Phagosomes of Live Macrophages. Kelly JJ, Dalesandro BE, Liu Z, Chordia MD, Ongwae GM, Pires MM.Angew Chem Int Ed Engl. 2024 Jan 15;63(3):e202313870.

Amidation of glutamate residues in mycobacterial peptidoglycan is essential for cell wall cross-linking. Shaku MT, Ocius KL, Apostolos AJ, Pires MM, VanNieuwenhze MS, Dhar N, Kana BD.Front Cell Infect Microbiol. 2023 Aug 24;13:1205829.

A Metabolic-Tag-Based Method for Assessing the Permeation of Small Molecules Across the Mycomembrane in Live Mycobacteria. Liu Z, Lepori I, Chordia MD, Dalesandro BE, Guo T, Dong J, Siegrist MS, Pires MM.Angew Chem Int Ed Engl. 2023 May 8;62(20):e202217777.

Immunotargeting of Gram-Positive Pathogens via a Cell Wall Binding Tick Antifreeze Protein. Dalesandro BE, Pires MM.J Med Chem. 2023 Jan 12;66(1):503-515.

Measurement of Small Molecule Accumulation into Diderm Bacteria. Ongwae GM, Lepori I, Chordia MD, Dalesandro BE, Apostolos AJ, Siegrist MS, Pires MM.ACS Infect Dis. 2023 Jan 13;9(1):97-110.