The Global Antimicrobial Resistance Crisis and Africa's Heavy Burden

Antimicrobial resistance (AMR), the phenomenon where bacteria, viruses, fungi, and parasites evolve to withstand drugs designed to kill them, poses one of the greatest threats to modern medicine. In South Africa and across Africa, the crisis is particularly acute due to high infection rates, limited access to diagnostics, and overuse of antibiotics in both human and animal health. Gram-negative bacteria, characterized by their double membrane structure that makes them harder to penetrate with drugs, are among the most dangerous culprits. Klebsiella pneumoniae, a gram-negative pathogen, stands out as a leading cause of AMR-related deaths worldwide, often causing pneumonia, bloodstream infections, urinary tract infections, and sepsis in hospitals.

Recent data underscores the severity: In the WHO African Region, one in five infections is resistant to antibiotics, with resistance to gram-negative bacteria exceeding 70% in many cases. South Africa alone saw 77,784 deaths from bacterial infections, 35,054 associated with bacterial AMR, and 8,485 directly attributed to it in recent estimates. These figures highlight why innovative research leadership from institutions like Stellenbosch University is vital for regional and global health security.

The traditional model of antibiotic discovery—inhibiting essential bacterial processes like protein synthesis or cell wall formation—has faltered as pathogens develop resistance mechanisms. This has led to a 'discovery void,' with few new classes of antibiotics entering the market in decades. Enter novel paradigms like targeted protein degradation, which Prof Erick Strauss and his team are pioneering at Stellenbosch University.

Launch of the Gr-ADI Consortium: A Game-Changer in Antibiotic Research

The Gram-Negative Antibiotic Discovery Innovator (Gr-ADI) consortium represents a landmark collaboration, funded by a US$60 million grant from the Bill & Melinda Gates Foundation, Novo Nordisk Foundation, and Wellcome. Spanning three years, it supports 18 innovative projects across 17 countries, marking the first investment from a broader $300 million global health R&D partnership launched in 2024. Unlike siloed efforts, Gr-ADI emphasizes open data sharing among teams, funders, and industry to accelerate breakthroughs against gram-negative pathogens.

Only two African teams were selected, underscoring the continent's underrepresentation in such initiatives despite bearing a disproportionate AMR burden. Prof Strauss's project, 'Exploring BacPROTACs as a New Paradigm for Antibacterial Discovery,' exemplifies the consortium's focus on transformative mechanisms. By pooling resources and learnings, Gr-ADI aims to deliver preclinical candidates that could refill the antibiotic pipeline, offering hope for infections untreatable by current drugs.

Prof Erick Strauss: Pioneering Chemical Biology at Stellenbosch University

🔬 Prof Erick Strauss, Professor and Head of the Department of Biochemistry in Stellenbosch University's Faculty of Science, brings decades of expertise to this leadership role. Also co-director of the Africa Centre for Therapeutic Innovation (ACTI), Strauss specializes in chemical biology, mechanistic enzymology, antimicrobial drug design & discovery, and biocatalysis. His lab delves into the chemistry and biology of coenzyme A (CoA)—a vital metabolic cofactor—and thiol-dependent redox processes, applying these insights to pathogens like Mycobacterium tuberculosis (causing tuberculosis, TB) and Plasmodium falciparum (malaria).

Strauss's career trajectory reflects a commitment to African health challenges. Educated with a PhD in biochemistry, he has built international collaborations, including with groups in the US, Spain, Italy, and Australia. His work has produced numerous publications on ResearchGate, focusing on enzyme inhibitors as antimicrobials. This foundation enabled his 2023 Gates Foundation and LifeArc grant under the Grand Challenges African Drug Discovery Accelerator (GC ADDA) for BacPROTACs against drug-resistant TB—a direct precursor to the Gr-ADI project.

"We are excited to be joining the Gr-ADI consortium, and to be able to contribute to solutions to health challenges for which Africa carries an especially heavy burden," Strauss stated. His leadership positions Stellenbosch—and South African higher education—as a hub for cutting-edge therapeutic innovation.

Decoding BacPROTACs: The Innovative Protein Degradation Approach

BacPROTACs, or bacterial proteolysis targeting chimeras, adapt targeted protein degradation (TPD) from cancer therapeutics to antibacterials. Traditional PROTACs (proteolysis targeting chimeras) are bifunctional molecules: one end binds a disease protein (e.g., oncogene), the other recruits the cell's ubiquitin-proteasome system to tag and degrade it. In bacteria lacking ubiquitination, BacPROTACs hijack the pathogen's endogenous proteases (enzymes that break down proteins) to destroy essential bacterial proteins.

Step-by-step process:

• A target-engaging ligand (TEL) binds a validated bacterial drug target or resistance factor.
• A linker connects it to a protease recruiter.
• The bifunctional molecule brings the target near the bacterium's protease (e.g., ClpXP system).
• The protease unfolds and degrades the target, killing or inhibiting the bacterium.
• The BacPROTAC is released and recycled—like a 'fishing rod with a baited hook'—enabling catalytic action at low doses with prolonged effects and lower resistance risk.

This paradigm shift promises antibiotics with novel mechanisms, bypassing existing resistance pathways. As Strauss notes, "What is especially exciting... is that the drug is recycled... suggesting that lower doses may be needed, and that the effects may be longer lasting."

The Multidisciplinary African Team Driving This Research

Strauss leads a powerhouse collaboration:

• Prof Andrew Whitelaw: SU Department of Medical Microbiology—expertise in pathogen diagnostics and resistance profiling.
• Prof Adrienne Edkins: Rhodes University—protein folding and degradation specialist.
• Dr Miquel Duran-Frigola: Ersilia Open-Source Initiative, Spain—computational chemistry for ligand design.
• Prof Willem van Otterlo: SU Chemistry—organic synthesis support.

This blend of microbiology, biochemistry, computation, and synthesis exemplifies interdisciplinary higher education research at its best. For aspiring researchers, Stellenbosch's model highlights opportunities in research jobs across African universities.

Targeting Klebsiella Pneumoniae: A Priority Pathogen in South Africa

Klebsiella pneumoniae, a gram-negative opportunistic pathogen, thrives in healthcare settings, causing hospital-acquired infections with mortality rates up to 50% in resistant cases. In South Africa, it contributes significantly to AMR deaths, exacerbated by carbapenem-resistant strains. Strauss's workflow will screen for BacPROTACs degrading key targets like beta-lactamases (resistance enzymes) or essential proteases.

| Key Challenges | BacPROTAC Advantages |

From TB Success to Gram-Negative Frontiers

Strauss's Gr-ADI project builds directly on 2023 GC ADDA funding for TB BacPROTACs, validating the platform against multi-drug-resistant mycobacteria. This stepwise expansion—from intracellular gram-positives/mycobacteria to tough gram-negatives—demonstrates rigorous progression. ACTI, co-directed by Strauss, further bolsters SU's drug discovery infrastructure for Africa-specific needs.

The three-year timeline includes hit identification, optimization, and preclinical validation, with open sharing accelerating global progress. Collaborations like Ersilia's AI-driven design exemplify how computational tools enhance experimental efficiency.

Implications for South African Higher Education and Healthcare

This leadership elevates Stellenbosch University's global profile in biomedical research, attracting talent and funding. For South Africa, potential BacPROTACs could address hospital infection crises, reducing healthcare costs and mortality. Broader impacts include training PhD students and postdocs in advanced chemical biology—key for postdoc opportunities.

Stakeholder perspectives: Health experts hail Gr-ADI as vital amid SA's AMR surveillance gaps; policymakers see it as bolstering National Health Insurance (NHI) goals. Challenges remain—scaling synthesis, regulatory hurdles—but Strauss's track record inspires confidence.

Photo by Grant Durr on Unsplash

Future Outlook: Catalyzing a New Era in Antibiotic Development

Over the next three years, expect milestones: validated BacPROTACs, expanded targets, and clinical candidate nominations. Long-term, Gr-ADI could spawn spinouts, with ACTI positioning Africa in biotech. Strauss envisions reusable platforms for diverse pathogens, transforming AMR management.

For academics eyeing this field, resources like crafting a winning academic CV and Rate My Professor aid career navigation. Explore university jobs and higher ed jobs for roles in infectious disease research.