Membrane pores: from structure and assembly, to medicine and technology

Gilbert, Robert J.C.; Bayley, Hagan; Anderluh, Gregor

doi:10.1098/rstb.2016.0208

Cited by 14 publications

(18 citation statements)

References 17 publications

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“…Some of these interactions have developed over time as a result of an evolutionary co-existence and adaptation [82]. Bacterial proteins, from symbiotic or pathogenic bacteria, interact with cell receptors of host cells, create pores in the membranes, modify the host cell environment (i.e., toxins), affect cell longevity, and stimulate different cell pathways during infection, among other functions [83,84,85,86,87,88]. They can cause an extensive rewiring of the host cell signaling network, creating a high impact on its health.…”

Section: Targeting Non-essential Processes: the Key To Overcome Rementioning

confidence: 99%

Thinking Outside the Bug: Molecular Targets and Strategies to Overcome Antibiotic Resistance

Monserrat-Martinez

Gambin

Sierecki

2019

IJMS

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Since their discovery in the early 20th century, antibiotics have been used as the primary weapon against bacterial infections. Due to their prophylactic effect, they are also used as part of the cocktail of drugs given to treat complex diseases such as cancer or during surgery, in order to prevent infection. This has resulted in a decrease of mortality from infectious diseases and an increase in life expectancy in the last 100 years. However, as a consequence of administering antibiotics broadly to the population and sometimes misusing them, antibiotic-resistant bacteria have appeared. The emergence of resistant strains is a global health threat to humanity. Highly-resistant bacteria like Staphylococcus aureus (methicillin-resistant) or Enterococcus faecium (vancomycin-resistant) have led to complications in intensive care units, increasing medical costs and putting patient lives at risk. The appearance of these resistant strains together with the difficulty in finding new antimicrobials has alarmed the scientific community. Most of the strategies currently employed to develop new antibiotics point towards novel approaches for drug design based on prodrugs or rational design of new molecules. However, targeting crucial bacterial processes by these means will keep creating evolutionary pressure towards drug resistance. In this review, we discuss antibiotic resistance and new options for antibiotic discovery, focusing in particular on new alternatives aiming to disarm the bacteria or empower the host to avoid disease onset.

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Section: Targeting Non-essential Processes: the Key To Overcome Rementioning

confidence: 99%

Thinking Outside the Bug: Molecular Targets and Strategies to Overcome Antibiotic Resistance

Monserrat-Martinez

Gambin

Sierecki

2019

IJMS

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“…This could also lead to the development of more effective therapeutics against bacteria that produce membrane attacking PFTs. 7 Previously, we have shown that pPorA self-assembled as an octamer in the SDS PAGE and gel extracted octamer readily inserted into planar lipid bilayers and formed stable cation-selective pores. 33,34,48 In contrast to pPorA, the pPorU peptides run on an SDS-PAGE gel formed only monomers, indicating the absence of self-assembled stable oligomers.…”

Section: Discussionmentioning

confidence: 93%

Decoding assembly of alpha-helical transmembrane pores through intermediate states

Puthumadathil

Nair

Krishnan

et al. 2021

Preprint

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Membrane-active pore-forming alpha-helical peptides and proteins are well known for their dynamic assembly mechanism and it has been critical to delineate the pore-forming structures in the membrane. Previously, attempts have been made to elucidate their assembly mechanism and there is a large gap due to complex pathways by which these membrane-active pores impart their effect. Here we demonstrate the multi-step structural assembly pathway of alpha-helical peptide pores formed by a 37 amino-acid synthetic peptide, pPorU based on the natural porin from Corynebacterium urealyticum using single-channel electrical recordings. More specifically, we report detectable intermediates states during membrane insertion and pore formation of pPorU. The fully assembled pore is functional and exhibited unusually large stable conductance and voltage-dependent gating, generally applicable to a range of pore-forming proteins. Furthermore, we used rationally designed mutants to understand the role of specific amino acids in the assembly of these peptide pores. Mutant peptides that differ from wild-type peptides produced noisy, unstable intermediate states and low conductance pores, demonstrating sequence specificity in the pore-formation process supported by molecular dynamics simulations. We suggest that our study contributes to understanding the mechanism of action of alpha-helical pores and antimicrobial peptides and should be of broad interest to bioengineers to build peptide-based nanopore sensors.

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“…In nature, various nanometer-sized pores act as ion channels, porins, aquaporins, pore-forming toxins (PFTs), and viral pores. Most often, however, nanopore technology applications employ PFTs involved in immune or infection mechanisms [28]. One of the major advantages is that PFTs are expressed as soluble monomers; oligomerization and pore formation occur spontaneously upon contact with the membrane of the host [29][30][31].…”

Section: Introductionmentioning

confidence: 99%

Biological Nanopores: Engineering on Demand

Crnković

Srnko

Anderluh

2021

Life

Self Cite

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Nanopore-based sensing is a powerful technique for the detection of diverse organic and inorganic molecules, long-read sequencing of nucleic acids, and single-molecule analyses of enzymatic reactions. Selected from natural sources, protein-based nanopores enable rapid, label-free detection of analytes. Furthermore, these proteins are easy to produce, form pores with defined sizes, and can be easily manipulated with standard molecular biology techniques. The range of possible analytes can be extended by using externally added adapter molecules. Here, we provide an overview of current nanopore applications with a focus on engineering strategies and solutions.

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Membrane pores: from structure and assembly, to medicine and technology

Abstract: One contribution of 17 to a discussion meeting issue 'Membrane pores: from structure and assembly, to medicine and technology'.

Cited by 14 publications

References 17 publications

Thinking Outside the Bug: Molecular Targets and Strategies to Overcome Antibiotic Resistance

Thinking Outside the Bug: Molecular Targets and Strategies to Overcome Antibiotic Resistance

Decoding assembly of alpha-helical transmembrane pores through intermediate states

Biological Nanopores: Engineering on Demand

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