Abstract
Marine mussels achieve strong underwater adhesion by depositing mussel foot proteins (Mfps) that form coacervates during the protein secretion. However, the molecular mechanisms that govern ...the phase separation behaviors of the Mfps are still not fully understood. Here, we report that GK-16*, a peptide derived from the primary adhesive protein Mfp-5, forms coacervate in seawater conditions. Molecular dynamics simulations combined with point mutation experiments demonstrate that Dopa- and Gly- mediated hydrogen-bonding interactions are essential in the coacervation process. The properties of GK-16* coacervates could be controlled by tuning the strength of the electrostatic and Dopa-mediated hydrogen bond interactions via controlling the pH and salt concentration of the solution. The GK-16* coacervate undergoes a pH induced liquid-to-gel transition, which can be utilized for the underwater delivery and curing of the adhesives. Our study provides useful molecular design principles for the development of mussel-inspired peptidyl coacervate adhesives with tunable properties.
Flexible and transparent power sources are highly desirable in realizing next-generation all-in-one bendable, implantable, and wearable electronic systems. The developed power sources are either ...flexible but opaque or semitransparent but lack of flexibility. Therefore, there is increasing recognition of the need for a new concept of electrochemical device structure design that allows both high flexibility and transparency. In this paper, we present a new concept for electrochemical device designa two-dimensional planar comb-teeth architecture on PET substrateto achieve both high mechanical flexibility and light transparency. Two types of prototypesdye-sensitized solar cells and supercapacitorshave been fabricated as planar devices and demonstrated excellent device performance, such as good light transparency, excellent flexibility, outstanding multiple large bending tolerance, light weight, effective prevention of short circuits during bending, and high device integration with up-date microelectronics, compared to conventional sandwich structure devices. Our planar design provides an attractive strategy toward the development of flexible, semitransparent electrochemical devices for fully all-in-one elegant and wearable energy management.
Resistance or tolerance to traditional antibiotics is a challenging issue in antimicrobial chemotherapy. Moreover, traditional bactericidal antibiotics kill only actively growing bacterial cells, ...whereas nongrowing metabolically inactive cells are tolerant to and therefore "persist" in the presence of legacy antibiotics. Here, we report that the diarylurea derivative PQ401, previously characterized as an inhibitor of the insulin-like growth factor I receptor, kills both antibiotic-resistant and nongrowing antibiotic-tolerant methicillin-resistant
(MRSA) by lipid bilayer disruption. PQ401 showed several beneficial properties as an antimicrobial lead compound, including rapid killing kinetics, low probability for resistance development, high selectivity to bacterial membranes compared to mammalian membranes, and synergism with gentamicin. In contrast to well-studied membrane-disrupting cationic antimicrobial low-molecular-weight compounds and peptides, molecular dynamic simulations supported by efficacy data demonstrate that the neutral form of PQ401 penetrates and subsequently embeds into bacterial lipid bilayers more effectively than the cationic form. Lastly, PQ401 showed efficacy in both the
and
models of MRSA infection. These data suggest that PQ401 may be a lead candidate for repurposing as a membrane-active antimicrobial and has potential for further development as a human antibacterial therapeutic for difficult-to-treat infections caused by both drug-resistant and -tolerant
Membrane-damaging antimicrobial agents have great potential to treat multidrug-resistant or multidrug-tolerant bacteria against which conventional antibiotics are not effective. However, their therapeutic applications are often hampered due to their low selectivity to bacterial over mammalian membranes or their potential for cross-resistance to a broad spectrum of cationic membrane-active antimicrobial agents. We discovered that the diarylurea derivative compound PQ401 has antimicrobial potency against multidrug-resistant and multidrug-tolerant
PQ401 selectively disrupts bacterial membrane lipid bilayers in comparison to mammalian membranes. Unlike cationic membrane-active antimicrobials, the neutral form of PQ401 rather than its cationic form exhibits maximum membrane activity. Overall, our results demonstrate that PQ401 could be a promising lead compound that overcomes the current limitations of membrane selectivity and cross-resistance. Also, this work provides deeper insight into the design and development of new noncharged membrane-targeting therapeutics to combat hard-to-cure bacterial infections.
The opportunistic human pathogen Staphylococcus aureus can evade antibiotics by acquiring antibiotic resistance genes or by entering into a non-growing dormant state. Moreover, the particular ...circumstances of a specific infection site, such as acidity or anaerobicity, often weaken antibiotic potency. Decreased bacterial susceptibility combined with diminished antibiotic potency is responsible for high failure rates when treating S. aureus infections. Here, we report that the membrane-active antimicrobial agent nTZDpa does not only exhibit enhanced antibiotic activity against multidrug-resistant Gram-positive pathogens in acidic pH, but also retains antimicrobial potency under anaerobic conditions. This agent completely eradicated highly antibiotic-tolerant cells and biofilms formed by methicillin-resistant S. aureus at pH 5.5 at concentrations at which it was not potent at pH 7.4. Furthermore, nTZDpa was more potent at synergistically potentiating gentamicin killing against antibiotic-tolerant MRSA cells at low pH than at high pH. All-atom molecular dynamics simulations combined with membrane-permeabilization assays revealed that the neutral form of nTZDpa, which contains carboxylic acid, is more effective than the deprotonated form at penetrating the bacterial membrane and plays an essential role in membrane activity. An acidic pH increases the proportion of the neutrally charged nTZDpa, which results in antimicrobial enhancement. Our results provide key insights into rational design of pH-sensitive membrane-active antimicrobials and antibiotic adjuvants that are effective in an infection environment. These findings demonstrate that nTZDpa is a promising lead compound for developing new therapeutics against hard-to-cure infections caused by drug-resistant and -tolerant S. aureus.
•Membrane-active nTZDpa shows enhanced antimicrobial activity in acidic conditions.•nTZDpa exhibits enhanced killing of antibiotic-tolerant persister cells at low pH.•Non-ionized neutral nTZDpa penetrates and embeds into bacterial lipid bilayers.•The proportion of neutral nTZDpa increases as pH decreases.•The antimicrobial synergism of nTZDpa plus gentamicin is enhanced at low pH.
Infections caused by Staphylococcus aureus, notably methicillin‐resistant S. aureus (MRSA), pose treatment challenges due to its ability to tolerate antibiotics and develop antibiotic resistance. The ...former, a mechanism independent of genetic changes, allows bacteria to withstand antibiotics by altering metabolic processes. Here, a potent methylazanediyl bisacetamide derivative, MB6, is described, which selectively targets MRSA membranes over mammalian membranes without observable resistance development. Although MB6 is effective against growing MRSA cells, its antimicrobial activity against MRSA persisters is limited. Nevertheless, MB6 significantly potentiates the bactericidal activity of gentamicin against MRSA persisters by facilitating gentamicin uptake. In addition, MB6 in combination with daptomycin exhibits enhanced anti‐persister activity through mutual reinforcement of their membrane‐disrupting activities. Crucially, the “triple” combination of MB6, gentamicin, and daptomycin exhibits a marked enhancement in the killing of MRSA persisters compared to individual components or any double combinations. These findings underscore the potential of MB6 to function as a potent and selective membrane‐active antimicrobial adjuvant to enhance the efficacy of existing antibiotics against persister cells. The molecular mechanisms of MB6 elucidated in this study provide valuable insights for designing anti‐persister adjuvants and for developing new antimicrobial combination strategies to overcome the current limitations of antibiotic treatments.
This study presents MB6, a methylazanediyl bisacetamide derivative, as a potent antimicrobial agent selectively targeting MRSA membranes. MB6 demonstrates triple synergistic killing against MRSA persisters by promoting gentamicin uptake and enhancing the membrane‐disrupting activity of daptomycin. This positions MB6 as a promising adjuvant in combating antibiotic‐resistant and ‐tolerant infections, offering innovative strategies in antimicrobial treatments.
The original version of this Article was incorrectly labelled as a ‘Review Article’. This has now been corrected to ‘Article’ in both the HTML and PDF versions.
The lipid bilayer membrane is increasingly recognized as a promising target for medicine, as exemplified by the recent surge in the development of membrane targeting antimicrobials (MTAs) against ...methicillin-resistant Staphylococcus aureus (MRSA), a superbug posing significant challenges to public health. Interestingly, the effectiveness of MTAs seems to vary markedly between the exponential growth and stationary phases of bacteria, a phenomenon that remains poorly understood. Here, we perform molecular dynamics (MD) simulations of the lipid bilayer membrane of S. aureus across different phases of bacteria growth, examining equilibrium properties and free energies associated with pore nucleation, the initial stage of membrane perforation preceding pore expansion and rupture. Our findings reveal that pore nucleation in the stationary phase bacterial membrane requires more energy compared to the exponential phase due to the increased concentration of cardiolipin, a type of mechanically resilient lipids, in the former, which provides a physical explanation for why the stationary phase is more tolerant of MTAs. The insights gained from this study not only deepen our understanding of the mechanics of bacterial membrane but can also help lay a foundation for simulation-assisted discovery and evaluation of MTAs for optimized treatments.
•Atomistic models are developed to investigate the properties of bacterial lipid membranes across different growth phases.•Variations in lipid compositions across different growth phases can result in different lipid distributions.•Pore nucleation energy of bacterial membrane is greater in the stationary phase compared to the exponential phase.•The strength of bacterial membrane in the stationary phase can be tuned by the lipid composition.
Understanding the interaction of 2D materials including graphene, boron nitride and MoS2 with biological systems is a growing topic of interest to many applications such as biosensors, drug delivery, ...gene therapy and nano-toxicity. In this paper, we show that the interaction of 2D materials with cellular membranes at its early stage of approaching is dominantly controlled by entropic forces. Recent experiments indicate that graphene sheets, depending on their size, can either undergo a near-orthogonal cutting or a parallel attachment mode of interaction with cell membranes. Here, we perform a set of integrated theoretical statistical mechanics analysis and coarse-grained molecular dynamics simulations to quantify the entropic energy barrier for these modes of interactions. Our results indicate that micro-sized graphene sheets prefer approaching a fluctuating membrane through a sharp corner, while nano-sized sheets are more likely to adhere to the cell membrane surface due to relatively low entropic energy cost that is comparable with thermal energy from random Brownian motions.
•The interaction of 2D nanomaterials with biological systems is studied in this paper.•This interaction is dominantly controlled by entropic forces.•The entropic forces and energetic costs are calculated for two modes of interactions.•We show that micro-sized sheets always approach a cell membrane in perpendicular mode.
Recent experiments have shown that certain molecular agents can selectively penetrate and aggregate in bacterial lipid membranes, leading to their permeability and rupture. To help reveal and ...understand the underlying mechanisms, here we establish a theory to show that the deformation energy of the membrane tends to limit the growth of molecular domains on a lipid membrane, resulting in a characteristic domain size, and that the domain aggregation significantly reduces the energy barrier to pore growth. Coarse-grained molecular dynamics simulations are performed to validate such domain aggregation and associated pore formation. This study sheds light on how lipid membranes can be damaged through molecular domain aggregation and contributes to establish a theoretical foundation for the next-generation membrane-targeting nanomedicine.
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