Stellenbosch University Leads $60M Gr-ADI Global Antibiotic Discovery Initiative

In a groundbreaking development for global health, Stellenbosch University (SU) has positioned itself at the forefront of the battle against antimicrobial resistance (AMR) through its leadership in the Gram-Negative Antibiotic Discovery Innovator (Gr-ADI) consortium. Professor Erick Strauss, Head of the Department of Biochemistry at SU, is spearheading one of only two African teams selected for this prestigious US$60 million initiative funded by the Bill & Melinda Gates Foundation, Novo Nordisk Foundation, and Wellcome.9392 This collaborative effort unites 18 research projects across 17 countries, marking the first investment from a larger $300 million global health research and development partnership launched in 2024.

The urgency of this work cannot be overstated. AMR claims 1.27 million lives annually worldwide from bacterial infections alone, with an additional 4.95 million associated deaths, and projections warn of up to 10 million deaths per year by 2050 if new antibiotics are not developed. Gram-negative bacteria like Klebsiella pneumoniae, the primary target here, are particularly notorious for their outer membrane that shields them from most existing drugs, leading to high resistance rates.60

The Gr-ADI Consortium: A Global Alliance Against Superbugs

The Gr-ADI consortium represents a paradigm shift in antibiotic research. Managed by RTI International, it fosters unprecedented data-sharing among funders and teams to accelerate early-stage discovery of novel antibiotics effective against Gram-negative pathogens. Unlike traditional siloed efforts, Gr-ADI emphasizes open collaboration to tackle the innovation drought—no new antibiotic classes for Gram-negatives have emerged in decades.50

For South Africa and Africa, where AMR burdens are heaviest due to limited access to advanced treatments and high infection rates, SU's involvement is transformative. Africa accounts for some of the highest resistance rates globally; for instance, third-generation cephalosporin resistance in K. pneumoniae exceeds 70% in parts of the continent.62 Strauss's selection underscores Africa's rising research prowess.

The three-year funding will support hit identification, validation, and preclinical optimization, with the goal of producing broad-spectrum drugs suitable for syndromic management in resource-limited settings.

🔬 Prof Erick Strauss's Revolutionary BacPROTACs Approach

At the heart of SU's project is a novel strategy borrowed from cancer therapy: Bacterial PROteolysis TArgeting Chimeras (BacPROTACs). These bifunctional molecules consist of a target-binding warhead linked to a ligand that recruits the bacterial ClpXP protease complex. Once bound, the pathogen's own degradation machinery destroys essential proteins or resistance factors, effectively committing 'molecular suicide'.93

Step-by-step, the process works as follows:

• A BacPROTAC molecule binds to a specific essential bacterial protein via its warhead.
• The linked ligand simultaneously engages the E3 ubiquitin ligase equivalent in bacteria (ClpXP).
• The protease unfolds and degrades the target protein, releasing the BacPROTAC for reuse—like a fishing rod catching multiple fish.
• This catalytic action allows lower doses and prolonged efficacy, reducing resistance risk since it exploits the bacterium's housekeeping machinery.

Strauss explains: "What is especially exciting is that the drug is recycled... suggesting lower doses may be needed, and effects longer lasting." This builds on his 2022 publication describing BacPROTACs for mycobacteria and a 2023 Gates-funded tuberculosis project.92

Prior successes include fragment-based screening against Staphylococcus aureus enzymes, showcasing Strauss's lab expertise in target-based discovery.78

Tackling Klebsiella Pneumoniae: South Africa's AMR Nemesis

Klebsiella pneumoniae tops the WHO's critical priority pathogens list, causing pneumonia, urinary tract infections, bloodstream infections, and sepsis. In South Africa, over 50% of isolates resist first-line antibiotics, with carbapenem-resistant strains (CRKP) showing case fatality rates up to 56.5%. Colistin resistance is at 7.6%, leaving few options.6061

In hospital settings, CRKP prevalence reached 66.8% in recent studies, with annual rates climbing. Hypervirulent strains add to the threat. SU's focus here aligns perfectly with local needs, where poverty and overuse exacerbate resistance.

Check out Stellenbosch University's announcement for more.93

Photo by Eben Piater on Unsplash

SU's Stellar Team and Institutional Support

Strauss leads a powerhouse team: co-investigator Prof Andrew Whitelaw from SU's Department of Medical Microbiology provides clinical insights; Prof Adrienne Edkins from Rhodes University contributes protein expertise; Dr Miquel Duran-Frigola's Ersilia Open-Source Initiative (Spain) aids computational design; and Prof Willem van Otterlo handles synthesis.

This aligns with SU's new Africa Centre for Therapeutic Innovation (ACTI), launched to bridge drug discovery gaps for African diseases like TB and malaria. ACTI's transdisciplinary model enhances SU's biomedical capacity.80

For aspiring researchers, opportunities abound. Explore research jobs or postdoc positions in infectious disease fields at AcademicJobs.com.

Africa's Heavy AMR Burden and SU's Leadership

Africa faces disproportionate AMR impacts: sub-Saharan newborns suffer over 250,000 sepsis deaths yearly. Resistance to key drugs like cephalosporins hits 90% in some countries. South Africa's labs confirm shared resistance genes between clinical and environmental sources, underscoring stewardship needs.83

• High poverty drives misuse.
• Limited diagnostics delay targeted therapy.
• Weak regulation allows counterfeit drugs.

SU's Gr-ADI role elevates African voices globally, inspiring youth via programs like the Centre for Epidemic Response and Innovation (CERI).38

From TB to Gram-Negatives: Strauss's Track Record

Strauss's lab has pioneered anti-TB agents via similar degradation strategies. The Desmond Tutu TB Centre at SU complements this, tackling multi-drug-resistant TB prevalent in SA. VALIDATE Network milestones further bolster SU's infectious disease research ecosystem.22

Recent X buzz highlights excitement: posts from Cape Argus praise SU's push against resistance.81

Challenges, Solutions, and Future Outlook

Challenges include scaling BacPROTACs for clinical use, ensuring oral bioavailability, and navigating resistance evolution. Solutions: Gr-ADI's data platform and SU's ACTI infrastructure.

Outlook: Potential first-in-class drugs by 2030, boosting SA's biotech sector. Implications for higher ed: More funding, PhDs, collaborations. Visit career advice for research paths.

Photo by Spekboom on Unsplash

Career Opportunities in Antibiotic Research

This initiative opens doors for biochemists, microbiologists, and pharmacologists. SU's success attracts grants, fostering jobs in drug discovery. South African universities lead QS SSA rankings in research output.4476 Link up with Rate My Professor for insights on SU faculty or browse university jobs.

In summary, Stellenbosch University's Gr-ADI leadership heralds hope against AMR. Stay informed via higher education news and explore higher ed jobs, career advice, or professor ratings at AcademicJobs.com.