Tuberculosis Outer Member Transporters Open New Opportunities for Drugs and Diagnostics

Technology Overview

Dr. Christoph Grundner

Two long-standing mysteries about the bacterium that causes tuberculosis (TB) are closer to being solved by recent work by infectious disease expert Christoph Grundner, PhD, and other research groups.

The first puzzle the Grundner Lab contributed to solving was how Mycobacterium tuberculosis (Mtb) transports nutrients across its nearly impermeable outer membrane. This barrier contributes to the challenges of clearing Mtb infections by the immune system or with antibiotics, yet the barrier does not hinder passage of molecules that the cell needs. A second mystery was a large gene family of approximately 170 genes — nearly 10% of the genome’s coding capacity — with an unknown function. The genes encode a family of proline-glutamic acid (PE) and proline-proline-glutamic acid (PPE) proteins that are found mainly in pathogenic but not in nonpathogenic mycobacteria.

Research by the Grundner Lab, along with other studies, revealed that PE/PPE proteins are outer membrane channels. Dr. Grundner’s study on potential Mtb signaling systems that use calcium ions showed that PE/PPE proteins are selective transporters with specific substrate-binding capabilities. Mtb requires many of these transporters because each allows entry or exit of a different metabolite, nutrient or ion.

The Grundner Lab also demonstrated that in addition to nutrients, several PE/PPE proteins are the likely channel through which anti-TB drugs, including amikacin and isoniazid, enter the bacterial cell. The Grundner team used genome-wide association analyses to identify mutations in the Mtb pe/ppe genes that are associated with antibiotic resistance in patients who have TB. The researchers then re-created the mutations in drug-susceptible laboratory strains of Mtb to prove the causal connection between specific PE/PPE channels and resistance to specific antibiotics. These studies identified a new class of drug resistance factors that could broadly affect the efficacy of many TB drugs.

Dr. Grunder is interested in industry partnerships to support continued investigations of PE/PPE proteins, including:

• Further exploration of PE/PPE mutations that are associated with TB drug resistance. These studies could identify diagnostic markers of resistance and PE/PPE domains that interact with substrates. These domains could be targeted to facilitate entry of modified drugs, perhaps hitched to the transporter’s specific substrate.
• Investigation of potential PE/PPE drug efflux functions in Mtb drug resistance.
• Structural analyses of PE/PPE proteins to identify features and domains to exploit in developing new drugs.

For conducting these and other studies, potentially in collaboration with industry partners, Dr. Grundner has expertise in:

• Systems analyses including comparisons of whole genome sequences and RNA-seq expression data to identify pe/ppe genes associated with drug resistance. The Grundner Lab has experience in overcoming analytic challenges stemming from the complex, repetitive sequences of PE/PPE genes.
• Advanced protein structure analyses for determining the topology of PE/PPE proteins, which often form multiprotein complexes, to determine the mechanisms of transport and domains involved in substrate interactions and drug resistance.  

Stage of Development

• Preclinical in vitro

Partnering Opportunities

• Collaborative research and development
• Sponsored research agreement
• Consultation agreement
• Data access
• High-throughput screening

Learn More

• Christoph Grundner, PhD
• Grundner Lab
• Grundner Lab phosphosignaling research
• Seattle Children’s Featured Research – Outer membrane proteins

Publications

1. Boradia V, Chen J, Frando A … Grundner C. PE/PPE proteins contribute to Mycobacterium tuberculosis drug resistance. Nat Commun. 2026. 24 April 2026
2. Boradia V, Frando A, Grundner C. The Mycobacterium tuberculosis PE15/PPE20 complex transports calcium across the outer membrane. PLOS Biol. 2022;20(11):e3001906.

Last updated May 2026