Mark Arnold Thomas Blaskovich

The minimum inhibitory concentration (MIC) assay is the gold standard for evaluating antimicrobial activity. However, conventional agar-based MIC methods often underestimate the potency of physicochemically complex compounds[1, 2]. Hydrophobic and adhesive molecules, such as lipoglycopeptide antibiotics, exhibit poor diffusion and non-specific binding to agar, leading to artificially elevated MIC values compared to broth-based methods[3]. This issue complicates accurate potency assessment, and is particularly an issue when attempting resistance frequency (FOR) studies, which must be conducted on solid media. Here, we developed a modified miniaturised agar MIC assay using 1% agarose, 0.002% Tween 80-supplemented tryptic soy broth (TSB), and a 24-well plate format[4]. These modifications improved compound dispersion, reduced matrix interactions, and lowered compound requirements. The optimised assay was validated with vancomycin, oritavancin, and dalbavancin against Staphylococcus aureus ATCC 43300 (MRSA) and Streptococcus pneumoniae ATCC 700677. This efficient, cost-effective, high-throughput platform overcomes the limitations of traditional agar methods, enhancing reliability in evaluating challenging antimicrobials and supporting next-generation antibiotic development.

1. The continual emergence of antibacterial resistance, combined with the limited development of novel and long-lasting effective antibiotics, has escalated bacterial infections into a serious glob...

The octapeptins are a set of 18 closely related natural product cyclic lipopeptides with broad spectrum activity against Gram-negative bacteria, including polymyxin-resistant strains. Within this class, only four congeners have been synthesized and/or tested in pure form, prompting us to investigate all 18 individual members. Here, we describe their chemical synthesis, which required the preparation of a series of chiral β-hydroxy fatty acids followed by solid-phase peptide synthesis and solution-phase cyclization. The series was tested against a panel of polymyxin-sensitive and -resistant Gram-negative pathogens, with minimum inhibitory concentrations of 2-8 μg/mL for most members. Oct-B5 and Oct-C0, two analogues possessing structural features disparate from those of the rest of the series, were shown to be inactive against the same panel of bacteria. Antifungal activity was also tested. This study demonstrates the first systematic synthesis and antimicrobial testing of a complete set of octapeptin natural product lipopeptides.

Nanocellulose directs the formation and immobilisation of ultrasmall copper nanoparticles on PP nonwovens, creating a porous, durable coating with rapid broad-spectrum antibacterial and antiviral activity, including at high humidity.

The escalating spread of multidrug-resistant (MDR) Gram-negative pathogens, particularly Pseudomonas aeruginosa , Klebsiella pneumoniae , and Acinetobacter baumannii , has severely undermined the efficacy of polymyxin B, one of the few remaining last-line antibiotics. Here, we identify hyperforin, a natural product derived from Hypericum perforatum , as a potent polymyxin B adjuvant capable of restoring its antibacterial activity against clinical Gram-negative isolates with high-level polymyxin resistance. Using a suite of in vitro assays, including fractional inhibitory concentration index, time-kill kinetics, biofilm eradication, membrane integrity assays, and ultrastructural imaging of the bacterial outer membrane, we show that hyperforin significantly enhances polymyxin B-mediated bacterial killing. Microscopy and N -phenyl-1-naphthylamine uptake are consistent with membrane perturbation, and increased intracellular reactive oxygen species is consistent with oxidative stress under combination treatment. Taken together, these orthogonal readouts support a working model of complementary membrane perturbation and oxidative stress. Remarkably, the observed synergistic effects occur at concentrations potentially achievable in the epithelial lining fluid of the lungs, providing a testable rationale for localized lung delivery (e.g., via a dry-powder inhaler). These findings unveil a promising therapeutic strategy that repurposes a bioactive phytochemical to potentiate polymyxins against otherwise untreatable polymyxin-resistant MDR Gram-negative infections.

Antimicrobial resistance, both bacterial and fungal, is a serious threat to global health. The rise in the level of resistant microorganisms has been accompanied by a decline in the level of development of new antibiotics over the past three decades, exacerbating the crisis. Novel chemotypes acting on new targets are particularly desirable. As outlined in this Perspective, organoselenium compounds are an overlooked class of molecules that represent a potential solution to some of these issues. We present here a comprehensive overview of the structures and activities of organoselenium compounds reported to have antimicrobial activity. The diversity of structures and activity profiles supports the hypothesis that further investigation of these compounds is justified, with the Se atom bestowing increased activity on otherwise unremarkable molecules. Concerns over potential Se toxicity appear unwarranted, with organoselenium compounds successfully dosed in humans in gram quantities. With the research community struggling to discover effective antibiotics, organoselenium derivatives warrant a closer look.

CDK-based PROTAC therapeutics are a promising new approach in oncology. In this microperspective, we summarize the landscape of anticancer PROTAC development targeting the CDK family as of 2024. We discuss the applications and outcomes of computational screening, alternative degradation strategies, different linkers, SAR, and the use of new E3 ligases. Finally, we explore the potential to enhance pharmacokinetic properties through the incorporation of different linkers in heterobifunctional molecules.

Covering: January 2014–June 2025. Previous review: Natural Product Reports, 2014, 31, 1612 Natural products (NPs) have long been foundational in medicine, from ancient herbal remedies to the discovery of transformative drugs like morphine and quinine. The mid-20th century marked a ‘golden age’ for antibiotic discovery from natural sources, which then expanded into other therapeutic areas. However, by the late 20th century, other technological advances had shifted NPs from being a central component of the discovery process to one of several options. This review explores the current role of NPs in pharmaceuticals by analysing NP-derived (NP-D) drugs approved since 2014 and clinical candidates in development as of the end of 2024. 58 NP-related drugs launched between January 2014 and June 2025 were identified, which included 45 NP and NP-D new chemical entities (NCEs) and 13 NP-antibody drug conjugates (NP-ADCs). Next, all 579 drugs—388 (67%) of which were NCEs and 191 (33%) were new biological entities (NBEs)—approved globally from 2014 to 2024 were analysed. In total, 56 (9.7%) of these 579 drugs were classified as NPs or NP-Ds using this review's NP definition: 44 NCEs (7.6% overall; 11.3% of NCEs) and 12 NP-ADCs (2.1% overall; 6.3% of NBEs). The number of new NP-D NCEs and NP-ADCs has fluctuated between 0 and 8 annually since 2014, with an average of five approvals per year. Next, 125 NP and NP-D compounds were identified that were undergoing clinical trials or in the registration phase at the end of December 2024. Thirty-three new pharmacophores not previously found in approved drugs are now in development; however, only one has been discovered in the past 15 years. This review highlights the enduring promise of NPs, despite their diminished role in drug discovery, and advocates for renewed emphasis on bioassay-guided isolation and mode of action studies to identify new drug leads.