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Antibiotic Resistance Characteristics of $\textit{Mycobacterium}$ $\textit{Abscessus}$ Rely on Specific Outer Membrane Porins and Surface-Associated Glycopeptidolipids

Luthra, Sakshi. Antibiotic Resistance Characteristics of $\textit{Mycobacterium}$ $\textit{Abscessus}$ Rely on Specific Outer Membrane Porins and Surface-Associated Glycopeptidolipids. 2024, University of Zurich, Faculty of Science.

Abstract

“Mycobacterium abscessus is an opportunistic pathogen, ubiquitous in the environment, that often causes infections in humans with compromised natural defences such as patients with cystic fibrosis or other chronic lung diseases. A current taxonomic classification suggests separation of M. abscessus into three distinct subspecies: M. abscessus subsp. abscessus, M. abscessus subsp. bolletii, and M. abscessus subsp. massiliense. Although a saprophyte in water and soil, following lung infection M. abscessus can swiftly grow and survive intra-cellularly within macrophages as well as in extra-cellular caseous lesions and airway mucus. Several factors contribute to the success of this rapidly growing mycobacterium. A plethora of intrinsic resistance mechanisms renders almost all clinically used antibiotics ineffective against M. abscessus. In addition, the presence of a highly dynamic open pan-genome in M. abscessus might explain the ease with which the bacterium evolves and adapts to a wide-spectrum of stressful environmental conditions encountered in diverse habitats. Importantly, the respiratory habitat of M. abscessus brings it in close proximity to highly virulent pathogens (for example, Pseudomonas aeruginosa in cystic fibrosis lung) which can serve as donors of novel drug resistance or virulence genes” (Luthra, S. et al.). “Mechanisms underpinning intrinsic drug resistance of M. abscessus are multi-fold and fall into two main groups: first, the presence of a highly impermeable cell envelope and/or multi-drug efflux pumps might reduce the effective concentration of antibiotics within the bacterial cells; second, the genome of M. abscessus encodes several putative enzymes which can inactivate antibiotics by modification and/or degradation or lower the affinity of the drug for its target by modifying the target. For long, molecular investigations aimed at elucidating antibiotic resistance mechanisms of M. abscessus were limited, however, significant progress has been made in recent years owing to the development of efficient tools for genetic manipulation of this bacterium” (Luthra, S. et al.). We examined, in this study, the role of limiting factors [i.e. β-barrel proteins that function as porins and surface-exposed glycopeptidolipids (GPL)] in regulating β-lactam transport across the mycomembrane and the impact of changes in cell envelope composition with or without the presence of a specific mechanism involved in β-lactam removal (i.e. deactivation by periplasmic β-lactamase) on the antibacterial susceptibility of M. abscessus toward a representative set of compounds from three different β-lactam subclasses (i.e. cephalosporins, carbapenems and a penem). This was accomplished through a series of gene knockouts (obtained via two-step homologous recombination) and by the determination of minimal inhibitory concentrations of antibiotics for all M. abscessus strains.

Here, we reveal that in M. abscessus, β-lactam susceptibility is linked to the presence of the general porin MapA and that the chromosomally encoded β-lactamase BlaMab can confer a higher level of β-lactam resistance in a mapA mutant than in wildtype M. abscessus. Additionally, the results suggest that the GPL environment can affect the levels of susceptibility to drugs that mainly diffuse across the membrane barrier through non-specific porins. This work has yielded new insights into the types and numbers of factors that influence susceptibility to β-lactam antibiotics in M. abscessus and how sets of genes act in concert, rather than in isolation, to elicit bacterial resistance to antibiotics. Through a better understanding of how the modification of cell envelope permeability elicits bacterial resistance, we might be able to develop new, effective means to overcome the ‘impermeability’ resistance strategy in an effort to fight M. abscessus infections. Reference Reproduced from Luthra, S. et al. The role of antibiotic-target-modifying and antibiotic-modifying enzymes in Mycobacterium abscessus drug resistance. Front. Microbiol. 9, 1–13 (2018) (see chapter 2).

Additional indexing

Item Type:Dissertation (monographical)
Referees:Sander Peter, Seeger Markus, Lehner Angelika
Communities & Collections:07 Faculty of Science > Department of Plant and Microbial Biology
UZH Dissertations
Dewey Decimal Classification:580 Plants (Botany)
Language:English
Place of Publication:Zürich
Date:21 March 2024
Deposited On:21 Mar 2024 15:28
Last Modified:11 Jul 2024 00:00
Number of Pages:131
OA Status:Green
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