Biology subjects

Kalsdorf, B.

Publications and source records attributed to Kalsdorf, B..

4 recordsLinked to original sources

bioRxiv2025

Robust antibiotic sensitization of pathogenic Pseudomonas aeruginosa via negative hysteresis in the cell envelope

Antibiotic combination in time and space is a key strategy to combat antimicrobial resistance. The success of such treatment designs requires their robust efficacy across treatment conditions and a pathogens genomic diversity. This study found that an initial treatment with a {beta}-lactam antibiotic causes robust cellular sensitization towards an aminoglycoside antibiotic across the high-risk human pathogen Pseudomonas aeruginosa, including resistant strains. This phenomenon of cellular sensitization, termed negative hysteresis, is modulated by the Cpx envelope stress response system and linked to membrane stress during growth. The increase in efficacy is achieved through a {beta}-lactam induced elevated cellular uptake of the subsequently administered aminoglycoside. Negative hysteresis and the Cpx system are linked in several cases to the expression of synergistic drug interactions, thus enhancing efficacy of antibiotic combinations. Overall, our study identifies the phenomenon of negative hysteresis as a robustly inducible phenotype and thus a unique focus for optimizing antimicrobial therapy.

evolutionary biology↗

bioRxiv2024

Serratia sp. dominates the lung microbiome of patients with tuberculosis and non-tuberculous mycobacterial lung diseases

BackgroundPathogenic mycobacteria, such as the Mycobacterium tuberculosis complex (Mtbc), and non-tuberculous mycobacteria (NTMs) can cause severe chronic pulmonary infections. However, not all infected patients develop active disease. Yet, it is unclear whether certain key taxa in the lung microbiome play a role in the pathogenesis of tuberculosis (TB) and NTM lung disease (LD). Material and methodsWe employed 16S rRNA amplicon sequencing (V3-V4) to characterize the baseline microbiome in bronchoalveolar lavage fluid from a patient cohort diagnosed with TB (n=23), NTM-LD (n=19), or non-infectious disease (n=4) prior to the initiation of therapy. The analysis included the depletion of human cells, removal of extracellular DNA, implementation of a decontamination strategy, and exploratory whole-metagenome sequencing (WMS) of selected specimens. ResultsThe genera Serratia and unclassified Yersiniaceae dominated the lung microbiome of all patients with a mean relative abundance of >15% and >70%, respectively. However, at the sub-genus level, as determined by amplicon sequence variants (ASVs), TB-patients exhibited increased community diversity, and TB specific ASV_7 (unclassified Yersiniaceae), and ASV_21 (Serratia) signatures. Exploratory analysis by WMS and ASV similarity analysis suggested the presence of Serratia liquefaciens, Serratia grimesii, Serratia myotis and/or Serratia quinivorans in both TB and NTM-LD patients. Overall, presence/absence of certain Serratia ASVs was significantly associated with disease state. ConclusionThe lung microbiome of TB patients harbors a distinct, and heterogenous microbiome structure with specific occurrences of certain Serratia traits. Serratia sp. plays a pivotal role in our understanding of microbial interactions in the lung microbiome of patients infected with Mtbc.

microbiology↗

bioRxiv2021

Tuberculostearic acid (TSA)-containing phosphatidylinositols as reliable marker to determine Mycobacterium tuberculosis bacterial burden

It is estimated that approximately one-fourth of the world's population is infected with strains of the Mycobacterium tuberculosis complex (MTBC), the causative agents of tuberculosis (TB). In this study, we present rationally developed molecular markers for bacterial burden, which are derived from mycobacterial phospholipids. Using lipidomic approaches, we show that tuberculostearic acid (TSA)-containing phosphatidylinositols (PI) are present in all clinically relevant MTBC lineages investigated. For the major abundant lipid PI 16:0_19:0 (TSA), a detection limit equivalent to 102 colony forming units (CFU) was determined for bacterial cultures and approximately 103 for cell culture systems. We further developed a mass spectrometry based targeted lipid assay, which - in contrast to bacterial quantification on solid medium - can be performed within several hours including sample preparation. Translation of this indirect and culture-free detection approach allowed the determination of pathogen loads in infected murine macrophages, human neutrophils and murine lung tissue. We show that marker lipids inferred from the mycobacterial PIs are increased in peripheral blood mononuclear cells (PBMCs) of TB patients beyond the lipid metabolic background in comparison to healthy controls. In a small cohort of drug-susceptible TB patients elevated levels of these marker molecules were detected at therapy start and declined following successful anti-tuberculosis treatment. The concentration of TSA-containing PIs can be used as correlate for reliable and rapid quantification of Mycobacterium tuberculosis (Mtb) burden in experimental in vitro model systems and may also provide a clinically relevant tool for monitoring TB therapy. One Sentence SummaryTuberculostearic acid containing phosphatidylinositols represent a novel, fast to measure, reliable correlate of Mycobacterium tuberculosis bacterial burden in experimental model systems, which makes a future clinical application conceivable.

biochemistry↗

bioRxiv2020

WNT6-ACC2-induced accumulation of triacylglycerol rich lipid droplets is exploited by Mycobacterium tuberculosis

In view of emerging drug-resistant tuberculosis, host directed therapies are urgently needed to improve treatment outcomes with currently available anti-tuberculosis therapies. One option is to interfere with the formation of lipid-laden “foamy” macrophages in the infected host. Here, we provide evidence that WNT6, a member of the evolutionary conserved WNT signaling pathway, promotes foam cell formation by regulating key lipid metabolic genes including acetyl-CoA carboxylase-2 (ACC2) during pulmonary TB. In addition, we demonstrate that Mycobacterium tuberculosis (Mtb) facilitates its intracellular growth and dissemination in the host by exploiting the WNT6-ACC2 pathway. Using genetic and pharmacological approaches, we show that lack of functional WNT6 or ACC2 significantly reduces intracellular TAG levels, Mtb growth and necrotic cell death of macrophages. In combination with the anti-TB drug isoniazid, pharmacological inhibition of ACC2 improved anti-mycobacterial treatment in vitro and in vivo. Therefore, we propose the WNT6-ACC2 signaling pathway as a promising target for a host-directed therapy to reduce intracellular replication of Mtb by modulating neutral lipid metabolism.Competing Interest StatementDrs. N. Reiling and J. Brandenburg (Research Center Borstel, Leibniz Lung Center, 23845 Borstel, Germany) have filed a patent application entitled ACC inhibitors as means and methods for treating mycobacterial diseases(WO2018007430A1, patent pending).View Full Text

immunology↗