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1. Antibacterial and Cytocompatible pH-Responsive Peptide Hydrogel

   https://doi.org/10.3390/molecules28114390  

   Edirisinghe, Dona_Imanga Upamadi; D’Souza, Areetha; Ramezani, Maryam; Carroll, Robert J; Chicón, Quenten; Muenzel, Cheyene L; Soule, Jonathan; Monroe, Mary_Beth Browning; Patteson, Alison E; Makhlynets, Olga V (June 2023, Molecules)

   A short peptide, FHHF-11, was designed to change stiffness as a function of pH due to changing degree of protonation of histidines. As pH changes in the physiologically relevant range, G′ was measured at 0 Pa (pH 6) and 50,000 Pa (pH 8). This peptide-based hydrogel is antimicrobial and cytocompatible with skin cells (fibroblasts). It was demonstrated that the incorporation of unnatural AzAla tryptophan analog residue improves the antimicrobial properties of the hydrogel. The material developed can have a practical application and be a paradigm shift in the approach to wound treatment, and it will improve healing outcomes for millions of patients each year. 

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2. Modular Design and Self‐assembly of pH‐Responsive Multidomain Peptides Incorporating Non‐natural Ionic Amino Acids

   https://doi.org/10.1002/chem.202403085  

   Asokan‐Sheeja, Haritha; Das, Debdatta; Nguyen, Jenny_N; Nguyen, Na; Van_Khanh_Pham, Tran; Nguyen, Kytai_T; Dong, He (November 2024, Chemistry – A European Journal)

   Abstract Stimuli‐responsive peptides, particularly pH‐responsive variants, hold significant promise in biomedical and technological applications by leveraging the broad pH spectrum inherent to biological environments. However, the limited number of natural pH‐responsive amino acids within biologically relevant pH ranges presents challenges for designing rational pH‐responsive peptide assemblies. In our study, we introduce a novel approach by incorporating a library of non‐natural amino acids featuring chemically diverse tertiary amine side chains. Hydrophobic and ionic properties of these non‐natural amino acids facilitate their incorporation into the assembly domain when uncharged, and electrostatic repulsion promotes disassembly under lower pH conditions. Furthermore, we observed a direct relationship between the number of substitutions and the hydrophobicity of these amino acids, influencing their pH‐responsive properties and enabling rational design based on desired transitional pH ranges. The structure‐activity relationship of these pH‐responsive peptides was evaluated by assessing their antimicrobial properties, as their antimicrobial activity is triggered by the disassembly of peptides to release active monomers. This approach not only enhances the specificity and controllability of pH responsiveness but also broadens the scope of peptide materials in biomedical and technological applications. 

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3. Building a genome-based understanding of bacterial pH preferences

   https://doi.org/10.1126/sciadv.adf8998  

   Ramoneda, Josep; Stallard-Olivera, Elias; Hoffert, Michael; Winfrey, Claire C.; Stadler, Masumi; Niño-García, Juan Pablo; Fierer, Noah (April 2023, Science Advances)

   The environmental preferences of many microbes remain undetermined. This is the case for bacterial pH preferences, which can be difficult to predict a priori despite the importance of pH as a factor structuring bacterial communities in many systems. We compiled data on bacterial distributions from five datasets spanning pH gradients in soil and freshwater systems (1470 samples), quantified the pH preferences of bacterial taxa across these datasets, and compiled genomic data from representative bacterial taxa. While taxonomic and phylogenetic information were generally poor predictors of bacterial pH preferences, we identified genes consistently associated with pH preference across environments. We then developed and validated a machine learning model to estimate bacterial pH preferences from genomic information alone, a model that could aid in the selection of microbial inoculants, improve species distribution models, or help design effective cultivation strategies. More generally, we demonstrate the value of combining biogeographic and genomic data to infer and predict the environmental preferences of diverse bacterial taxa. 

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4. Heterosynaptic plasticity in biomembrane memristors controlled by pH

   https://doi.org/10.1557/s43577-022-00344-z  

   McClintic, William T.; Scott, Haden L.; Moore, Nick; Farahat, Mustafa; Maxwell, Mikayla; Schuman, Catherine D.; Bolmatov, Dima; Barrera, Francisco N.; Katsaras, John; Collier, C. Patrick (January 2023, MRS Bulletin)

   Abstract In biology, heterosynaptic plasticity maintains homeostasis in synaptic inputs during associative learning and memory, and initiates long-term changes in synaptic strengths that nonspecifically modulate different synapse types. In bioinspired neuromorphic circuits, heterosynaptic plasticity may be used to extend the functionality of two-terminal, biomimetic memristors. In this article, we explore how changes in the pH of droplet interface bilayer aqueous solutions modulate the memristive responses of a lipid bilayer membrane in the pH range 4.97–7.40. Surprisingly, we did not find conclusive evidence for pH-dependent shifts in the voltage thresholds ( V* ) needed for alamethicin ion channel formation in the membrane. However, we did observe a clear modulation in the dynamics of pore formation with pH in time-dependent, pulsed voltage experiments. Moreover, at the same voltage, lowering the pH resulted in higher steady-state currents because of increased numbers of conductive peptide ion channels in the membrane. This was due to increased partitioning of alamethicin monomers into the membrane at pH 4.97, which is below the pKa (~5.3–5.7) of carboxylate groups on the glutamate residues of the peptide, making the monomers more hydrophobic. Neutralization of the negative charges on these residues, under acidic conditions, increased the concentration of peptide monomers in the membrane, shifting the equilibrium concentrations of peptide aggregate assemblies in the membrane to favor greater numbers of larger, increasingly more conductive pores. It also increased the relaxation time constants for pore formation and decay, and enhanced short-term facilitation and depression of the switching characteristics of the device. Modulating these thresholds globally and independently of alamethicin concentration and applied voltage will enable the assembly of neuromorphic computational circuitry with enhanced functionality. Impact statement We describe how to use pH as a modulatory “interneuron” that changes the voltage-dependent memristance of alamethicin ion channels in lipid bilayers by changing the structure and dynamical properties of the bilayer. Having the ability to independently control the threshold levels for pore conduction from voltage or ion channel concentration enables additional levels of programmability in a neuromorphic system. In this article, we note that barriers to conduction from membrane-bound ion channels can be lowered by reducing solution pH, resulting in higher currents, and enhanced short-term learning behavior in the form of paired-pulse facilitation. Tuning threshold values with environmental variables, such as pH, provide additional training and learning algorithms that can be used to elicit complex functionality within spiking neural networks. Graphical abstract 

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5. Targeting peptide‐based quorum sensing systems for the treatment of gram‐positive bacterial infections

   https://doi.org/10.1002/pep2.24298  

   Milly, Tahmina A.; Tal‐Gan, Yftah (November 2022, Peptide Science)

   Abstract Bacteria utilize a cell density‐dependent communication system called quorum sensing (QS) to coordinate group behaviors. In Gram‐positive bacteria, QS involves the production of and response to auto‐inducing peptide (AIP) signaling molecules to modulate group phenotypes, including pathogenicity. As such, this bacterial communication system has been identified as a potential therapeutic target against bacterial infections. More specifically, developing synthetic modulators derived from the native peptide signal paves a new way to selectively block the pathogenic behaviors associated with this signaling system. Moreover, rational design and development of potent synthetic peptide modulators allows in depth understanding of the molecular mechanisms that drive QS circuits in diverse bacterial species. Overall, studies aimed at understanding the role of QS in microbial social behavior could result in the accumulation of significant knowledge of microbial interactions, and consequently lead to the development of alternative therapeutic agents to treat bacterial infectivity. In this review, we discuss recent advances in the development of peptide‐based modulators to target QS systems in Gram‐positive pathogens, with a focus on evaluating the therapeutic potential associated with these bacterial signaling pathways. 

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