Biology subjects

Maurer, F. P.

Publications and source records attributed to Maurer, F. P..

5 recordsLinked to original sources

bioRxiv2022

Novel synergies and isolate specificities in the drug interactions landscape of Mycobacterium abscessus

Mycobacterium abscessus infections are difficult to treat and are often considered untreatable without tissue resection. Due to the intrinsic drug-resistant nature of the bacteria, combination therapy of three or more antibiotics is recommended. A major challenge in treating M. abscessus infections is the absence of a universal combination therapy with satisfying clinical success rates, leaving clinicians to treat infections using antibiotic lacking efficacy data. We systematically measured drug combinations in M. abscessus to establish a resource of drug interaction data and identify patterns of synergy to help design optimized combination therapies. We measured approximately 230 pairwise drug interactions among 22 antibiotics and identified 71 synergistic pairs, 54 antagonistic pairs, and four potentiator-antibiotics not previously reported. We found that commonly used drug combinations in the clinic, such as azithromycin and amikacin, are antagonistic in lab reference strain ATCC19977, whereas novel combinations, such as azithromycin and rifampicin, are synergistic. Another challenge in developing universally effective multidrug therapies for M. abscessus is the significant variation in drug response between isolates. We measured drug interactions in a focused set of 36 drug pairs across a small panel of clinical isolates with rough and smooth morphotypes. We observed highly strain-dependent drug interactions that cannot be predicted from single-drug susceptibility profiles or known drug mechanisms of action. Our study demonstrates the immense potential to identify synergistic drug combinations in the vast drug combination space and emphasizes the importance of strain-specific combination measurements for designing improved therapeutic interventions.

microbiology↗

bioRxiv2021

C25-modified rifamycin derivatives with improved activity against Mycobacterium abscessus

Infections caused by Mycobacterium abscessus are difficult to treat due to its intrinsic resistance to most antibiotics. Formation of biofilms and the capacity of M. abscessus to survive inside host phagocytes further complicate eradication. Herein, we explored whether addition of a carbamate-linked group at the C25 position of rifamycin SV blocks enzymatic inactivation by ArrMab, an ADP-ribosyltransferase conferring resistance to rifampicin. Unlike rifampicin, 5j, a benzyl piperidine rifamycin derivative with a morpholino substituted C3 position, is not modified by purified ArrMab. Additionally, we show that the ArrMab D82 residue is essential for catalytic activity. Thermal profiling of ArrMab in the presence of 5j, rifampicin or rifabutin shows that 5j does not bind to ArrMab. We found that the activity of 5j is comparable to amikacin against M. abscessus planktonic cultures and pellicles. Critically, 5j also exerts potent antimicrobial activity against M. abscessus in human macrophages and shows synergistic activity with amikacin and azithromycin.

microbiology↗

bioRxiv2020

In silico secretome characterization of clinical Mycobacterium abscessus isolates provides insights into antigenic differences

Mycobacterium abscessus (MAB) is a widely disseminated pathogenic non-tuberculous mycobacterium (NTM). Like with M. tuberculosis complex (MTBC), excreted / secreted (ES) proteins play an essential role for its virulence and survival inside the host. ES proteins contain highly immunogenic proteins, which are of interest for novel diagnostic assays and vaccines. Here, we used a robust bioinformatics pipeline to predict the secretome of the M. abscessus ATCC 19977 reference strain and fifteen clinical isolates belonging to all three MAB subspecies, M. abscessus subsp. abscessus, M. abscessus subsp. bolletii, and M. abscessus subsp. massiliense. We found that ~18% of the proteins encoded in the MAB genomes were predicted as secreted and that the three MAB subspecies shared > 85 % of the predicted secretomes. MAB isolates with a rough (R) colony morphotype showed larger predicted secretomes than isolates with a smooth (S) morphotype. Additionally, proteins exclusive to the secretomes of MAB R variants had higher antigenic densities than those exclusive to S variants, independently of the subspecies. For all investigated isolates, ES proteins had a significantly higher antigenic density than non-ES proteins. We identified 337 MAB ES proteins with homologues in previously investigated M. tuberculosis secretomes. Among these, 222 have previous experimental support of secretion, and some proteins showed homology with protein drug targets reported in the DrugBank database. The predicted MAB secretomes showed a higher abundance of proteins related to quorum-sensing and Mce domains as compared to MTBC indicating the importance of these pathways for MAB pathogenicity and virulence. Comparison of the predicted secretome of M. abscessus ATCC 19977 with the list of essential genes revealed that 99 secreted proteins corresponded to essential proteins required for in vitro growth. All predicted secretomes were deposited in the Secret-AAR web-server (http://microbiomics.ibt.unam.mx/tools/aar/index.php).

bioinformatics↗

bioRxiv2020

Insertion and deletion evolution reflects antibiotics selection pressure in a Mycobacterium tuberculosis outbreak.

In genome evolution, genetic variants are the source of diversity, which natural selection acts upon. Treatment of human tuberculosis (TB) induces a strong selection pressure for the emergence of antibiotic resistance in the infecting Mycobacterium tuberculosis (MTB) strains. MTB evolution in response to treatment has been intensively studied and mainly attributed to point substitutions. However, the contribution of insertions and deletions (indels) to MTB genome evolution remains poorly understood. Here, we analyzed a multi-drug resistant MTB outbreak for the presence of high-quality indels and substitutions. We find that indels are significantly enriched in genes conferring antibiotic resistance. Furthermore, we show that indels are inherited during the outbreak and follow a molecular clock with an evolutionary rate of 5.37e-9 indels/site/year, which is 23x lower compared to the substitution rate. Inherited indels may co-occur with substitutions in genes along related biological pathways; examples are iron storage and resistance to second-line antibiotics. This suggests that epistatic interactions between indels and substitutions affect antibiotic resistance and compensatory evolution in MTB. Author summaryMycobacterium tuberculosis (MTB) is a human pathogen causing millions of deaths every year. Its genome evolution has been intensively characterized through point substitutions, i.e., nucleotide exchanges that are inherited. Additional mutations are short or long insertions and deletions of nucleotides, termed indels. Short indels in genes might change the reading frame and disrupt the gene product. Here we show that antibiotic treatment has a strong impact on indel evolution in an MTB outbreak. Namely, indels occur frequently in genes causing antibiotic resistance upon disruption. Furthermore, we show that the molecular clock, i.e., the temporal emergence of variants over time, holds for short indels in MTB genomes. Finally, we observe that indels may co-occur with substitutions in genes along related biological pathways. These results support the notion that indels are important contributors to MTB evolution. We anticipate that including indels in the analyses of MTB outbreaks will improve our understanding of antibiotic resistance evolution.

microbiology↗

bioRxiv2019

Improving tuberculosis surveillance by detecting international transmission using publicly available whole-genome sequencing data

IntroductionImproving the surveillance of tuberculosis (TB) is especially important for multidrug-resistant (MDR) and extensively drug-resistant (XDR)-TB. The large amount of publicly available whole-genome sequencing (WGS) data for TB gives us the chance to re-use data and to perform additional analysis at a large scale. AimWe assessed the usefulness of raw WGS data of global MDR/XDR-TB isolates available from public repositories to improve TB surveillance. MethodsWe extracted raw WGS data and the related metadata of Mycobacterium tuberculosis isolates available from the Sequence Read Archive. We compared this public dataset with WGS data and metadata of 131 MDR- and XDR-TB isolates from Germany in 2012-2013. ResultsWe aggregated a dataset that includes 1,081 MDR and 250 XDR isolates among which we identified 133 molecular clusters. In 16 clusters, the isolates were from at least two different countries. For example, cluster2 included 56 MDR/XDR isolates from Moldova, Georgia, and Germany. By comparing the WGS data from Germany and the public dataset, we found that 11 clusters contained at least one isolate from Germany and at least one isolate from another country. We could, therefore, connect TB cases despite missing epidemiological information. ConclusionWe demonstrated the added value of using WGS raw data from public repositories to contribute to TB surveillance. By comparing the German and the public dataset, we identified potential international transmission events. Thus, using this approach might support the interpretation of national surveillance results in an international context.

microbiology↗