Ca2+-Daptomycin targets cell wall biosynthesis by forming a tripartite complex with undecaprenyl-coupled intermediates and membrane lipids

Grein, Fabian; Müller, Anna; Scherer, Katharina M.; Liu, Xinliang; Ludwig, Kevin C.; Klöckner, Anna; Strach, Manuel; Sahl, Hans‐Georg; Kubitscheck, Ulrich; Schneider, Tanja

doi:10.1038/s41467-020-15257-1

Cited by 152 publications

(191 citation statements)

References 66 publications

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“…For example, in bacteria, ILs could bind or destabilize the peptidoglycan structure, which could affect the ability of the relevant enzyme to synthesize it, or in a complementary way, they could alter the function of the enzymes responsible to the synthesis of the cell wall (e.g., peptidoglycan). Similar MoAs have been observed for antibiotics (Ling et al 2015 ; Batson et al 2017 ; Grein et al 2020 ). More in general, ILs could interfere with active transporters also by affecting the conversion from adenosine diphosphate (ADP) to adenosine triphosphate (ATP), for example, by directly binding ADP/ATP.…”

Section: Mechanisms Of Action Of Ilssupporting

confidence: 77%

Mechanisms of action of ionic liquids on living cells: the state of the art

2020

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Ionic liquids (ILs) are a relatively new class of organic electrolytes composed of an organic cation and either an organic or inorganic anion, whose melting temperature falls around room-temperature. In the last 20 years, the toxicity of ILs towards cells and micro-organisms has been heavily investigated with the main aim to assess the risks associated with their potential use in (industrial) applications, and to develop strategies to design greener ILs. Toxicity, however, is synonym with affinity, and this has stimulated, in turn, a series of biophysical and chemical-physical investigations as well as few biochemical studies focused on the mechanisms of action (MoAs) of ILs, key step in the development of applications in bio-nanomedicine and bio-nanotechnology. This review has the intent to present an overview of the state of the art of the MoAs of ILs, which have been the focus of a limited number of studies but still sufficient enough to provide a first glimpse on the subject. The overall picture that emerges is quite intriguing and shows that ILs interact with cells in a variety of different mechanisms, including alteration of lipid distribution and cell membrane viscoelasticity, disruption of cell and nuclear membranes, mitochondrial permeabilization and dysfunction, generation of reactive oxygen species, chloroplast damage (in plants), alteration of transmembrane and cytoplasmatic proteins/enzyme functions, alteration of signaling pathways, and DNA fragmentation. Together with our earlier review work on the biophysics and chemical-physics of IL-cell membrane interactions (Biophys. Rev. 9:309, 2017), we hope that the present review, focused instead on the biochemical aspects, will stimulate a series of new investigations and discoveries in the still new and interdisciplinary field of “ILs, biomolecules, and cells.”

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Section: Mechanisms Of Action Of Ilssupporting

confidence: 77%

Mechanisms of action of ionic liquids on living cells: the state of the art

2020

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“…Daptomycin is a lipopeptide antibiotic acting on bacterial CM 10,11 . Membrane depolarization and ion leakage can be observed when the positively charged Ca 2+ -DAP forms a complex with the negatively charged hydrophilic head group of PG and bactoprenol-bound cell wall precursor in CM 11,12,52 . Therefore, phenotypic alteration of membrane surface charges via mprF mutation is a commonly reported bacterial evolution to resist positively charged drugs, such as CAMPs and DAP 12,39,50,51 .…”

Section: Discussionmentioning

confidence: 99%

Association of mprF mutations with cross-resistance to daptomycin and vancomycin in methicillin-resistant Staphylococcus aureus (MRSA)

Thitiananpakorn

Aiba

Tan

et al. 2020

Sci Rep

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We first reported a phenomenon of cross-resistance to vancomycin (VCM) and daptomycin (DAP) in methicillin-resistant Staphylococcus aureus (MRSA) in 2006, but mechanisms underlying the cross-resistance remain incompletely understood. Here, we present a follow-up study aimed to investigate genetic determinants associated with the cross-resistance. Using 12 sets of paired DAP susceptible (DAPS) and DAP non-susceptible (DAPR) MRSA isolates from 12 patients who had DAP therapy, we (i) assessed susceptibility to DAP and VCM, (ii) compared whole-genome sequences, (iii) identified mutations associated with cross-resistance to DAP and VCM, and (iv) investigated the impact of altered gene expression and metabolic pathway relevant to the cross-resistance. We found that all 12 DAPR strains exhibiting cross-resistance to DAP and VCM carried mutations in mprF, while one DAPR strain with reduced susceptibility to only DAP carried a lacF mutation. On the other hand, among the 32 vancomycin-intermediate S. aureus (VISA) strains isolated from patients treated with VCM, five out of the 18 strains showing cross-resistance to DAP and VCM carried a mprF mutation, while 14 strains resistant to only VCM had no mprF mutation. Moreover, substitution of mprF in a DAPS strain with mutated mprF resulted in cross-resistance and vice versa. The elevated lysyl-phosphatidylglycerol (L-PG) production, increased positive bacterial surface charges and activated cell wall (CW) synthetic pathways were commonly found in both clinical isolates and laboratory-developed mutants that carry mprF mutations. We conclude that mprF mutation is responsible for the cross-resistance of MRSA to DAP and VCM, and treatment with DAP is more likely to select for mprF-mediated cross-resistance than is with VCM.

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“…While in this case the activity and mechanism of action of the labeled compound were not notably compromised (Wenzel et al, 2014), it is well-possible that the addition Müller et al, 2016b;Grein et al, 2020 of a metallocene tag will influence the behavior of the compound in one way or another. However, metallocenes are still considerably smaller than common fluorescence labels and thus less likely to severely change the antibiotic properties of a molecule.…”

Section: Metal Labelingmentioning

confidence: 80%

“…However, the true complexity of bacterial membranes cannot be mimicked, since not only the composition, but also the physicochemical properties vary drastically from species to species, between different growth conditions, between media, and growth phases. It has become apparent that model membrane studies are not enough to truly describe the complex nature of AMP-membrane interactions, the most prominent example being daptomycin (Pogliano et al, 2012;Müller et al, 2016b;Gray and Wenzel, 2020a;Grein et al, 2020). This realization together with the growing interest in microbial membrane architecture (Jones et al, 2001;Lopez and Kolter, 2010; Barák and Muchová, 2013;Bramkamp and Lopez, 2015;Strahl and Errington, 2017) has prompted the development of a variety of in vivo techniques to analyze membrane physiology in living bacteria.…”

Section: Cytoplasmic Membranementioning

confidence: 99%

A How-To Guide for Mode of Action Analysis of Antimicrobial Peptides

Schäfer

Wenzel

2020

Front. Cell. Infect. Microbiol.

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Antimicrobial peptides (AMPs) are a promising alternative to classical antibiotics in the fight against multi-resistant bacteria. They are produced by organisms from all domains of life and constitute a nearly universal defense mechanism against infectious agents. No drug can be approved without information about its mechanism of action. In order to use them in a clinical setting, it is pivotal to understand how AMPs work. While many pore-forming AMPs are well-characterized in model membrane systems, non-pore-forming peptides are often poorly understood. Moreover, there is evidence that pore formation may not happen or not play a role in vivo. It is therefore imperative to study how AMPs interact with their targets in vivo and consequently kill microorganisms. This has been difficult in the past, since established methods did not provide much mechanistic detail. Especially, methods to study membrane-active compounds have been scarce. Recent advances, in particular in microscopy technology and cell biological labeling techniques, now allow studying mechanisms of AMPs in unprecedented detail. This review gives an overview of available in vivo methods to investigate the antibacterial mechanisms of AMPs. In addition to classical mode of action classification assays, we discuss global profiling techniques, such as genomic and proteomic approaches, as well as bacterial cytological profiling and other cell biological assays. We cover approaches to determine the effects of AMPs on cell morphology, outer membrane, cell wall, and inner membrane properties, cellular macromolecules, and protein targets. We particularly expand on methods to examine cytoplasmic membrane parameters, such as composition, thickness, organization, fluidity, potential, and the functionality of membrane-associated processes. This review aims to provide a guide for researchers, who seek a broad overview of the available methodology to study the mechanisms of AMPs in living bacteria.

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Ca2+-Daptomycin targets cell wall biosynthesis by forming a tripartite complex with undecaprenyl-coupled intermediates and membrane lipids

Cited by 152 publications

References 66 publications

Mechanisms of action of ionic liquids on living cells: the state of the art

Mechanisms of action of ionic liquids on living cells: the state of the art

Association of mprF mutations with cross-resistance to daptomycin and vancomycin in methicillin-resistant Staphylococcus aureus (MRSA)

A How-To Guide for Mode of Action Analysis of Antimicrobial Peptides

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