Addressing the challenge of antimicrobial resistance
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Discovery of new AMR drugs targeting modulators of antimicrobial activity using in vivo silkworm screening systems
Global concerns about drug-resistant bacteria have underscored the need for new antimicrobial drugs. Emerging strategies in drug discovery include considering the third factors that influence drug activity. These factors include host-derived elements, adjuvants, and drug combinations, which are crucial in regulating antimicrobial efficacy. Traditional in vivo assessments have relied on animal models to study drug absorption, distribution, metabolism, excretion, and toxicity (ADMET). Alternative models, such as silkworms, are being explored to overcome the ethical and financial barriers associated with mammalian models. The silkworm has been proven effective in evaluating ADMET and in highlighting the therapeutic potential enhanced by third factors. Host factors (either mammalian or non-mammalian) enhance the antimicrobial activity of antimicrobial agents such as lysocin E. Additionally, using d-cycloserine to potentiate vancomycin has successfully combated vancomycin-resistant infections in silkworms. Leveraging silkworms in drug discovery could establish a novel screening method incorporating interactions with third factors, whether host related or non-host-related, thus promising new pathways for identifying antimicrobial drugs with unique mechanisms of action.
Prevalence and transmission risk of colistin and multidrug resistance in long-distance coastal aquaculture
Due to the wide use of antibiotics, intensive aquaculture farms have been recognized as a significant reservoir of antibiotic resistomes. Although the prevalence of colistin resistance genes and multidrug-resistant bacteria (MDRB) has been documented, empirical evidence for the transmission of colistin and multidrug resistance between bacterial communities in aquaculture farms through horizontal gene transfer (HGT) is lacking. Here, we report the prevalence and transmission risk of colistin and multidrug resistance in 27 aquaculture water samples from 9 aquaculture zones from over 5000 km of subtropical coastlines in southern China. The colistin resistance gene mcr−1, mobile genetic element (MGE) intl1 and 13 typical antibiotic resistance genes (ARGs) were prevalent in all the aquaculture water samples. Most types of antibiotic (especially colistin) resistance are transmissible in bacterial communities based on evidence from laboratory conjugation and transformation experiments. Diverse MDRB were detected in most of the aquaculture water samples, and a strain with high-level colistin resistance, named Ralstonia pickettii MCR, was isolated. The risk of horizontal transfer of the colistin resistance of R. pickettii MCR through conjugation and transformation was low, but the colistin resistance could be steadily transmitted to offspring through vertical transfer. The findings have important implications for the future regulation of antibiotic use in aquaculture farms globally to address the growing threat posed by antibiotic resistance to human health.
Breaking barriers: we need a multidisciplinary approach to tackle cancer drug resistance
Most cancer-related deaths result from drug-resistant disease(1,2). However, cancer drug resistance is not a primary focus in drug development. Effectively mitigating and treating drug-resistant cancer will require advancements in multiple fields, including early detection, drug discovery, and our fundamental understanding of cancer biology. Therefore, successfully tackling drug resistance requires an increasingly multidisciplinary approach. A recent workshop on cancer drug resistance, jointly organised by Cancer Research UK, the Rosetrees Trust, and the UKRI-funded Physics of Life Network, brought together experts in cell biology, physical sciences, computational biology, drug discovery, and clinicians to focus on these key challenges and devise interdisciplinary approaches to address them. In this perspective, we review the outcomes of the workshop and highlight unanswered research questions. We outline the emerging hallmarks of drug resistance and discuss lessons from the COVID-19 pandemic and antimicrobial resistance that could help accelerate information sharing and timely adoption of research discoveries into the clinic. We envisage that initiatives that drive greater interdisciplinarity will yield rich dividends in developing new ways to better detect, monitor, and treat drug resistance, thereby improving treatment outcomes for cancer patients.
Resistance to linezolid in Staphylococcus aureus by mutation, modification, and acquisition of genes
Linezolid binds to the 50S subunit of the bacterial ribosome, inhibiting bacterial protein synthesis by preventing the formation of the initiation complex. Oxazolidinone antimicrobial drugs represent the last line of defense in treating Staphylococcus aureus infections; thus, resistance to linezolid in S. aureus warrants high priority. This article examines the major mechanisms of resistance to linezolid in S. aureus, which include: mutations in the domain V of 23S rRNA (primarily G2576); chromosomal mutations in the rplC, rplD, and rplV genes (encoding the ribosomal uL3, uL4, and uL22 proteins, respectively); the exogenous acquisition of the methylase encoded by the chloramphenicol-florfenicol resistance (cfr) gene; the endogenous methylation or demethylation of 23S rRNA; the acquisition of optrA and poxtA resistance genes; and the existence of the LmrS multidrug efflux pump. In conclusion, these mechanisms mediate resistance through mutations or modifications to the bacterial target, thereby reducing the affinity of linezolid for the peptidyl transferase center (PTC) binding site or by preventing the binding of linezolid to the PTC through a ribosomal protective effect. The existence of additional, unexplained resistance mechanisms requires further investigation and verification.
Blue benzoquinone from scorpion venom shows bactericidal activity against drug-resistant strains of the priority pathogen Acinetobacter baumannii
Antibiotic-resistant bacteria pose a significant global health threat, particularly pathogens resistant to last-resort antibiotics, such as those listed as priority pathogens by the World Health Organization. Addressing this challenge requires the development of novel antimicrobial agents. Previously, we identified a blue 1,4-benzoquinone isolated from the venom of the Mexican scorpion Diplocentrus melici as a potent antimicrobial compound effective against Staphylococcus aureus and Mycobacterium tuberculosis. Moreover, we devised a cost-effective synthetic route for its production. In this study, we demonstrate that the blue benzoquinone exhibits antibacterial activity against additional pathogens, including the priority pathogen Acinetobacter baumannii. Notably, the compound effectively killed clinical strains of A. baumannii resistant to multiple antibiotics, including carbapenem and colistin. Furthermore, A. baumannii did not develop resistance to the benzoquinone even after multiple growth cycles under sub-inhibitory concentrations, unlike the tested antibiotics. These findings underscore the potential of this blue benzoquinone as a lead compound for the development of a new class of antibiotics targeting multidrug-resistant bacteria.
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