Tag: science

Rethinking Natural Products: What’s Next for Nature-Inspired Drug Discovery?

Introduction. Nature has been humanity’s pharmacy for millennia—think traditional herbal remedies, or blockbuster drugs like morphine and quinine. However, in recent decades, drug discovery focused has on alternative lead discovery methods and engineered biologics. In our new review (January 2014–June 2025) published in Natural Product Reports we ask: what is the current role of natural-product-derived (NP-D) compounds in drug approvals and clinical pipelines?

Link: https://doi.org/10.1039/D5NP00031A

The Big Picture:
– We identified 58 NP-related drugs launched globally between January 2014 and June 2025 (45 NCEs and 13 ADCs).
– Between 2014 and 2024, of the 579 drugs approved globally (388 NCEs, 191 NBEs) we found 56 (≈ 9.7 %) could be classified as NP or NP-D drugs.
– At the end of December 2024, there were 125 NP or NP-D compounds undergoing clinical trials or in the registration phase, including 33 new pharmacophores not previously seen in approved drugs. However, only one of these new pharmacophores in active clinical development has been discovered in the last 15 years.

Key Take-aways.

(1) Despite the decline in emphasis on natural products, they still contribute meaningfully (~10 %) to approved drugs.

(2) The pipeline is active—but innovation (in terms of new pharmacophores) is slow. – To unlock future NP-derived success, renewed emphasis on bioassay-guided isolation and mode-of-action elucidation is needed.

Why it Matters. For researchers, entrepreneurs and policymakers: natural products offer chemical diversity and biological relevance that synthetic libraries often struggle to match. Our review suggests that while NP-D compounds aren’t dominating the field, they remain a valuable strategic option. Re-investing in the foundational work (isolation, mechanism, natural-source exploration) could yield the next generation of breakthrough therapeutics.

Looking Ahead:

(1) Better integration of genomics, metabolomics and modern analytics with natural product discovery.

(2) Strategic partnerships between academia, industry and natural-source repositories to accelerate NP pipelines.

(3) Encourage early-phase investment in NP scaffolds and biologically-rich extracts.

(4) Further integration of machine learning, genomics, metabolomics and modern analytics with NP discovery.

Conclusion. Nature still holds surprises—and in the era of multi-drug resistant pathogens, complex diseases and the need for new therapeutic modalities, NP-derived drugs will continue to play an important role for the foreseeable future. I hope this review spurs renewed interest, investment and collaboration across the NP drug discovery ecosystem.

Zosurabalpin — a new class of Acinetobacter targeting antibiotic

The discovery, antibacterial profile, and mode of action (MoA) of zosurabalpin, which belongs to a new antibacterial class called ‘tethered macrocyclic peptides’ (MCPs), was recently disclosed in two Nature papers (here and here, as well as a commentary). Zosurabalpin is currently being evaluated in a phase 1 trial by Roche for the treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) infections. A. baumannii is classed a Priority Pathogen by the WHO and these infections, while being relatively rare at this moment in time, have high mortality and morbidity. These two papers are very detailed and this blog highlights only some of the work undertaken!

Hit Discovery: Whole-cell phenotypic screening of a 44,985 member MCP library identified a cluster of active MCPs. One of these hits, RO7036668, displayed selective activity against A. baumannii, but no cytotoxicity (promising).

Hit to lead to clinical candidate: Iterations of medicinal chemistry and testing led to the identification of MCPs such as RO7075573 with more potent in vitro and in vivo mouse model activity against A. baumannii; however, it was observed during pre-clinical toxicology studies that RO7075573 caused aggregation of low-density lipoprotein/high-density lipoprotein vesicles in rat plasma through an unknown mechanism. Using an in-house developed rat plasma precipitation assay, the team showed that zwitterionic (definition) tethered MCPs had significantly reduced plasma precipitation and zosurabalpin was ultimately selected for development. It had been previously shown that zwitterionic compounds can have enhanced Gram-negative bacterial membrane transport — see O’Shea & Moser and Muñoz & Hergenrother for discussions on bacterial entry.

Mode of action (MoA): Sequencing of resistant mutants suggested that the zosurabalpin’s target was likely to be the protein complex LptB2FGC, which is an ATP-binding cassette used by Gram-negative bacteria to move lipopolysaccharide (LPS) from their inner membrane to the outer layer of the outer membrane. It was shown that MCPs helped to trap LPS in the protein complex by several orthogonal methods including Cryo-EM.

Did you know that A. baumannii can survive without LPS in its outer membrane? Amazingly it can! It was shown that MCPs failed to inhibit the growth of LPS-deficient A. baumannii, which supported the proposed MoA. The LPS-deficient phenotype can be produced in response to polymyxin treatment, but there is a significant fitness cost, as well as increased susceptibility to other antibiotics and disinfectants.

Looking forward: Zosurabalpin has only just started its clinical development (safety and dosing). Although the total number of A. baumannii infections is (mercifully) relatively low, perhaps a multi-site, multi-country clinical strategy could be used in phase 3, similar to the trial successfully completed for the β-lactam and β-lactamase inhibitor combination sulbactam-durlobactam. Although it could be theoretically possible to undertake an Acinetobacter specific trial using rapid diagnostics, the frequency of polymicrobial infections in clinical settings could lead to the need for the development of combination therapies with other antibiotics with activity against other pathogens such as Pseudomonas, Klebsiella and E. coli, may be even MRSA. It will be interesting to what directions are taken.

Concluding remarks: The discovery and development of zosurabalpin and the unravelling of its clinically unexploited MoA is very impressive. Importantly, the team also included how they overcame development hurdles, which is very valuable information for antibacterial drug discoverers. Recent successful clinical trials have shown that it is possible to run multi-site, multi-country trials for these deadly Gram-negative infections and the approval of a novel class of antibiotics to treat CRAB infections will be welcomed by clinicians. Now the world needs to make sure that adequate funding is available for these types of phase 3 trials, as well as ensure that incentives such as the Pasteur Act or similar pull incentives are introduced as soon as possible. Otherwise, novel antibiotics with life saving potential may not make it to patients. Remember, paraphrasing Mike Tyson “Everyone has a plan until they get punched in the mouth a drug-resistant Gram-negative infection.”