Biology subjects

Ballmer, D.

Publications and source records attributed to Ballmer, D..

6 recordsLinked to original sources

bioRxiv2026

The antiparasitics ivermectin and moxidectin trigger genomic and transcriptomic adaptation in bacteria

The macrocyclic lactone anthelmintics ivermectin and moxidectin are widely used for parasite control and show antibacterial activity in vitro. Given their structural relatedness to macrolide antibiotics, their broad use raises concerns about macrolide cross-resistance and altered bacterial physiology, yet the impact on gut bacterial isolates and underlying mechanisms remains poorly defined. Here, we combined Oxford Nanopore whole genome sequencing with Illumina RNA sequencing across six bacterial isolates analyzed as unexposed controls and as derivatives repeatedly exposed to ivermectin or moxidectin to identify genomic and transcriptomic signatures associated with exposure to these drugs. High-quality genome assemblies enabled integrated analyses across species with distinct cellular architectures and antimicrobial resistance gene arsenals. Across the panel, exposure was associated with i) widespread modulation of ribosome-linked genes and pathways, the molecular target of macrolide antibiotics; ii) context-dependent tuning of pre-existing antimicrobial resistance gene arsenals, such as macB and mdlB; and iii) recurrent alterations in potassium transport systems (ktrA and trkA). These findings suggest that repeated ivermectin or moxidectin exposure can reshape bacterial physiology in ways that may, in specific genetic backgrounds, co-modulate resistance-associated traits.

microbiology↗

bioRxiv2025

Hybrid-metagenomics reveal off-target effects of albendazole, ivermectin-albendazole and moxidectin-albendazole on the human gut bacteria.

The human whipworm parasite, Trichuris trichiura, poses a critical public health problem, affecting over 400 million people globally and responding poorly to the standard-of-care - benzimidazole chemotherapy. Recent efforts aimed at developing improved treatment options, the two macrolide-benzimidazole combination therapies ivermectin-albendazole and moxidectin-albendazole. Recent reports suggest that ivermectin and moxidectin possess antibacterial properties in vitro, hence there is a need to comprehensively characterize their off-target effects on the gut microbiome. In the framework of a randomized-controlled trial we collected stool samples of 204 T. trichiura-infected individuals in Cote dIvoire receiving albendazole (400mg), albendazole-ivermectin (400mg/200{micro}g/kg) and albendazole-moxidectin (400mg/8mg). Using a state-of-the-art hybrid sequencing approach that combines Illumina short read and Oxford Nanopore long read shotgun sequencing, we recovered over 800 high-quality metagenome-assembled genomes. Our analyses reveal that albendazole and albendazole-moxidectin induce taxonomic shifts in the gut microbiota with only mild functional consequences. In contrast, in individuals receiving higher quantities of albendazole-ivermectin (ivermectin > 12mg), based on their weight, we observed profoundly modulated taxonomic composition and microbial function, while the resistome was largely spared. These findings robustly confirm ivermectins antibacterial properties in the human gut, extending beyond previously reported in vitro effects. Given that ivermectin is a cornerstone in parasitic disease control, it is crucial to evaluate its broader impacts and considering more targeted, evidence-based treatment strategies.

genomics↗

bioRxiv2024

An unconventional regulatory circuitry involving Aurora B controls anaphase onset and error-free chromosome segregation in trypanosomes

Accurate chromosome segregation during mitosis requires that all chromosomes establish stable bi-oriented attachments with the spindle apparatus. Kinetochores form the interface between chromosomes and spindle microtubules and as such are under tight control by complex regulatory circuitry. As part of the chromosomal passenger complex (CPC), the Aurora B kinase plays a central role within this circuitry by destabilizing improper kinetochore-microtubule attachments and relaying the attachment status to the spindle assembly checkpoint, a feedback control system that delays the onset of anaphase by inhibiting the anaphase-promoting complex/cyclosome. Intriguingly, Aurora B is conserved even in kinetoplastids, an evolutionarily divergent group of eukaryotes, whose kinetochores are composed of a unique set of structural and regulatory proteins. Kinetoplastids do not have a canonical spindle checkpoint and it remains unclear how their kinetochores are regulated to ensure the fidelity and timing of chromosome segregation. Here, we show in Trypanosoma brucei, the kinetoplastid parasite that causes African sleeping sickness, that inhibition of Aurora B using an analogue-sensitive approach arrests cells in metaphase, with a reduction in properly bi-oriented kinetochores. Aurora B phosphorylates several kinetochore proteins in vitro, including the N-terminal region of the divergent Bub1-like protein KKT14. Depletion of KKT14 partially overrides the cell cycle arrest caused by Aurora B inhibition, while overexpression of a non-phosphorylatable KKT14 protein results in a prominent delay in the metaphase-to-anaphase transition. Finally, we demonstrate using a nanobody-based system that re-targeting the catalytic module of the CPC to the outer kinetochore is sufficient to promote mitotic exit but causes massive chromosome mis-segregation in anaphase. Our results indicate that the CPC and KKT14 are involved in an unconventional pathway controlling mitotic exit and error-free chromosome segregation in trypanosomes.

cell biology↗

bioRxiv2024

Kinetoplastid kinetochore proteins KKT14-KKT15 are divergent Bub1/BubR1-Bub3 proteins

Faithful transmission of genetic material is crucial for the survival of all organisms. In many eukaryotes, a feedback control mechanism called the spindle checkpoint ensures chromosome segregation fidelity by delaying cell cycle progression until all chromosomes achieve proper attachment to the mitotic spindle. Kinetochores are the macromolecular complexes that act as the interface between chromosomes and spindle microtubules. While most eukaryotes have canonical kinetochore proteins that are widely conserved, kinetoplastids such as Trypanosoma brucei have a seemingly unique set of kinetochore proteins including KKT1-25. Available evidence suggests that T. brucei lacks components of the spindle checkpoint and is unable to delay cell cycle progression in response to spindle defects. It therefore remains poorly understood how kinetoplastids regulate cell cycle progression or ensure chromosome segregation fidelity. Here, we report a crystal structure of the C-terminal domain of KKT14 from Apiculatamorpha spiralis and uncover that it is a pseudokinase. Its structure is most similar to the kinase domain of Bub1, a key component of the spindle checkpoint in other eukaryotes. In addition, KKT14 in T. brucei and other trypanosomatids has a putative ABBA motif that is present in Bub1 and its paralog BubR1. We also find that the N-terminal part of KKT14 interacts with KKT15, whose WD40 repeat beta-propeller is phylogenetically closely related to a direct interactor of Bub1/BubR1 called Bub3. Our findings indicate that KKT14-KKT15 are divergent orthologs of Bub1/BubR1-Bub3, which promote accurate chromosome segregation in trypanosomes.

cell biology↗

bioRxiv2023

Dynamic localization of the chromosomal passenger complex is controlled by the orphan kinesin KIN-A in the kinetoplastid parasite Trypanosoma brucei

The chromosomal passenger complex (CPC) is an important regulator of cell division, which shows dynamic subcellular localization throughout mitosis, including kinetochores and the spindle midzone. In traditional model eukaryotes such as yeasts and humans, the CPC consists of the catalytic subunit Aurora B kinase, its activator INCENP, and the localization module proteins Borealin and Survivin. Intriguingly, Aurora B and INCENP as well as their localization pattern are conserved in kinetoplastids, an evolutionarily divergent group of eukaryotes that possess a unique set of kinetochore proteins and lack homologs of Borealin or Survivin. It is not understood how the kinetoplastid CPC assembles or how it is targeted to its subcellular destinations during the cell cycle. Here, we identify two orphan kinesins, KIN-A and KIN-B, as bona fide CPC proteins in Trypanosoma brucei, the causative agent of African sleeping sickness. By employing biochemical, structural, and cell biological approaches, we demonstrate that KIN-A and KIN-B serve as the scaffold for the assembly of the remaining CPC subunits. Kinetochore localization of the CPC depends on the KKT7 - KKT8 complex pathway, with the C-terminal unstructured tail of KIN-A serving as a key interaction partner for the KKT8 complex. Our data therefore show that, unlike other eukaryotes that take advantage of histone modifications for centromere recruitment, trypanosomes rely on kinetochore proteins to recruit the CPC onto kinetochores. Furthermore, the ATPase activity of KIN-A promotes chromosome alignment in prometaphase and CPC translocation to the central spindle upon anaphase onset. Thus, KIN-A constitutes a unique two-in-one CPC localization module in complex with KIN-B, which directs the CPC to kinetochores (from S phase until metaphase) via its C-terminal tail, and to the central spindle (in anaphase) via its N-terminal kinesin motor domain. Our findings highlight the evolutionary diversity of CPC proteins and raise the possibility that kinesins may have served as the original transport vehicles for Aurora B kinases in early eukaryotes.

cell biology↗

bioRxiv2019

Successful mating and hybridisation in two closely related flatworm species despite significant differences in reproductive morphology and behaviour

Speciation is usually a gradual process, in which reproductive barriers between two species accumulate over time. Reproductive traits, like genital morphology and mating behaviour, are some of the fastest diverging characters and can serve as reproductive barriers. The free-living flatworm Macrostomum lignano, an established model for studying sex in hermaphrodites, and its congener M. janickei are closely related, but differ substantially in their male intromittent organ (stylet) morphology. Here, we examine whether these morphological differences are accompanied by differences in behavioural traits, and whether these could represent barriers to successful mating and hybridization between the two species. Our data shows that the two species differ in many aspects of their mating behaviour, with M. janickei having a five-fold longer copulation duration, copulating less frequently, and having a longer and more delayed suck behaviour (a postcopulatory behaviour likely involved in sexual conflict). Interestingly, and despite these significant morphological and behavioural differences, the two species mate readily with each other in heterospecific pairings, often showing behaviours of intermediate duration. Although both species have similar fecundity in conspecific pairings, the heterospecific pairings revealed clear postmating barriers, as only few heterospecific pairings produced F1 hybrids. These hybrids had a stylet morphology that was intermediate between that of the parental species, and they could successfully backcross to both parental species. Finally, in a mate choice experiment we tested if the worms preferentially mated with conspecifics over heterospecifics, since such a preference could represent a premating barrier. Interestingly, the experiment showed that the nearly two-fold higher mating rate of M. lignano caused it to mate more with conspecifics, leading to assortative mating, while M. janickei ended up mating more with heterospecifics. Thus, while the two species can hybridize, the mating rate differences could possibly lead to higher fitness costs for M. janickei compared to M. lignano.

animal behavior and cognition↗