Rachita Dash

Molecules. 2023 Mar 5;28(5):2383. doi: 10.3390/molecules28052383.

ABSTRACT

The study of peptides (synthetic or corresponding to discrete regions of proteins) has facilitated the understanding of protein structure-activity relationships. Short peptides can also be used as powerful therapeutic agents. However, the functional activity of many short peptides is usually substantially lower than that of their parental proteins. This is (as a rule) due to their diminished structural organization, stability, and solubility often leading to an enhanced propensity for aggregation. Several approaches have emerged to overcome these limitations, which are aimed at imposing structural constraints into the backbone and/or sidechains of the therapeutic peptides (such as molecular stapling, peptide backbone circularization and molecular grafting), therefore enforcing their biologically active conformation and thus improving their solubility, stability, and functional activity. This review provides a short summary of approaches aimed at enhancing the biological activity of short functional peptides with a particular focus on the peptide grafting approach, whereby a functional peptide is inserted into a scaffold molecule. Intra-backbone insertions of short therapeutic peptides into scaffold proteins have been shown to enhance their activity and render them a more stable and biologically active conformation.

PMID:36903628 | PMC:PMC10005171 | DOI:10.3390/molecules28052383

Microbiol Spectr. 2023 Mar 6:e0234422. doi: 10.1128/spectrum.02344-22. Online ahead of print.

ABSTRACT

Diabetic mellitus nephropathy (DMN) is a serious complication of diabetes and a major health concern. Although the pathophysiology of diabetes mellitus (DM) leading to DMN is uncertain, recent evidence suggests the involvement of the gut microbiome. This study aimed to determine the relationships among gut microbial species, genes, and metabolites in DMN through an integrated clinical, taxonomic, genomic, and metabolomic analysis. Whole-metagenome shotgun sequencing and nuclear magnetic resonance metabolomic analyses were performed on stool samples from 15 patients with DMN and 22 healthy controls. Six bacterial species were identified to be significantly elevated in the DMN patients after adjusting for age, sex, body mass index, and estimated glomerular filtration rate (eGFR). Multivariate analysis found 216 microbial genes and 6 metabolites (higher valine, isoleucine, methionine, valerate, and phenylacetate levels in the DMN group and higher acetate levels in the control group) that were differentially present between the DMN and control groups. Integrated analysis of all of these parameters and clinical data using the random-forest model showed that methionine and branched-chain amino acids (BCAAs) were among the most significant features, next to the eGFR and proteinuria, in differentiating the DMN group from the control group. Metabolic pathway gene analysis of BCAAs and methionine also revealed that many genes involved in the biosynthesis of these metabolites were elevated in the six species that were more abundant in the DMN group. The suggested correlation among taxonomic, genetic, and metabolic features of the gut microbiome would expand our understanding of gut microbial involvement in the pathogenesis of DMN and may provide potential therapeutic targets for DMN. IMPORTANCE Whole metagenomic sequencing uncovered specific members of the gut microbiota associated with DMN. The gene families derived from the discovered species are involved in the metabolic pathways of methionine and branched-chain amino acids. Metabolomic analysis using stool samples showed increased methionine and branched-chain amino acids in DMN. These integrative omics results provide evidence of the gut microbiota-associated pathophysiology of DMN, which can be further studied for disease-modulating effects via prebiotics or probiotics.

PMID:36877076 | DOI:10.1128/spectrum.02344-22

Chirality. 2023 Mar 8. doi: 10.1002/chir.23555. Online ahead of print.

ABSTRACT

Mammalian D-Cysteine is racemized from L-cysteine by serine racemase, a pyridoxal phosphate (PLP)-dependent enzyme. Endogenous D-Cysteine plays a role in neural development by inhibiting proliferation of neural progenitor cells (NPCs) via protein kinase B (AKT) signaling mediated by the FoxO family of transcription factors. D-Cysteine binds to Myristoylated Alanine Rich C Kinase Substrate (MARCKS) and alters phosphorylation at Ser 159/163 and its translocation from the membrane. By racemizing serine and cysteine, mammalian serine racemase may play important roles in neural development highlighting its importance in psychiatric disorders.

PMID:36890664 | DOI:10.1002/chir.23555

Chemistry. 2023 Mar 9:e202203624. doi: 10.1002/chem.202203624. Online ahead of print.

ABSTRACT

Peptide stapling represents a versatile strategy to generate peptide derivatives with stable helical structures. While a wide range of skeletons have been investigated for cyclizing the side chains of peptides, the stereochemical outcomes from the linkers remain to be better understood. In this study, we incorporated α-amino acids (α-AAs) as bridges to construct side chain-stapled analogs of an interleukin-17A-binding peptide (HAP) and evaluated the impacts of the staples on the peptide's properties. While all AA-derived peptidyl staples drastically increase the enzymatic stability of HAP, our results indicate that compared to the D-amino acid bridges, the L-AA-based staples may generate more significant impacts in increasing the helicity and enhancing the IL-17A-binding affinity of the modified peptide. Using Rosetta modelling and molecular dynamics (MD) simulations, we demonstrate that the chirality (L/D) possessed within the AAs substantially influences the conformation of stapled HAP peptides, providing either stabilizing or destabilizing effects. Based on the computational model, a modification of the stapled HAP leads to the discovery of a peptide with further enhanced helicity, enzymatic stability and IL-17A-inhibiting ability. This systematic study reveals that chiral AAs can serve as modulatory linkers for optimizing the structures and properties of stapled peptides.

PMID:36891840 | DOI:10.1002/chem.202203624

Infect Drug Resist. 2023 Feb 28;16:1203-1219. doi: 10.2147/IDR.S396566. eCollection 2023.

ABSTRACT

The prevalence of antimicrobial resistance (AMR) has been rising quickly in recent years. AMR has emerged as a significant obstacle to the treatment of infectious diseases, and many attempts have been made over the past decades to find the best antimicrobials to overcome it. Therefore, it is crucial to find new medicines to combat the global rise of AMR. Antimicrobial peptides (AMPs) and cell-penetrating peptides (CPPs), which target membranes, are promising antibiotic substitutes. AMPs and CPPs are short amino acid sequences with antibacterial activity as well as possible therapeutic benefits. In this review, we provide a thorough and systematic introduction to the advancement of research on AMPs and CPPs, including information on their classification, mechanism of action, current state of application, limitations and optimization.

PMID:36879855 | PMC:PMC9985452 | DOI:10.2147/IDR.S396566

Int J Pharm. 2023 Mar 6:122798. doi: 10.1016/j.ijpharm.2023.122798. Online ahead of print.

ABSTRACT

Chemical and enzymatic in vivo degradation of antimicrobial peptides represents a major challenge for their therapeutic use to treat bacterial infections. In this work, anionic polysaccharides were investigated for their ability to increase the chemical stability and achieve sustained release of such peptides. The investigated formulations comprised a combination of antimicrobial peptides (vancomycin (VAN) and daptomycin (DAP)) and anionic polysaccharides (xanthan gum (XA), hyaluronic acid (HA), propylene glycol alginate (PGA) and alginic acid (ALG)). VAN dissolved in buffer of pH 7.4 and incubated at 37 °C showed first order degradation kinetics with a reaction rate constant k_obs of 5.5 x 10^-2 day^-1 corresponding with a half-life of 13.9 days. However, once VAN was present in a XA, HA or PGA-based hydrogel, k_obs decreased to (2.1-2.3) x 10^-2 day^-1 while k_obs was not affected in an alginate hydrogel and a dextran solution (5.4 x 10^-2 and 4.4 x 10^-2 day^-1). Under the same conditions, XA and PGA also effectively decreased k_obs for DAP (5.6 x 10^-2 day^-1), whereas ALG had no effect and HA even increased the degradation rate. These results demonstrate that the investigated polysaccharides (except ALG for both peptides and HA for DAP) slowed down the degradation of VAN and DAP. DSC analysis was used to investigate on polysaccharide ability to bind water molecules. Rheological analysis highlighted that the polysaccharides containing VAN displayed an increase in G' of their formulations, pointing that the peptides interaction act as crosslinker of the polymer chains. The obtained results suggest that the mechanism of stabilization of VAN and DAP against hydrolytic degradation is conferred by electrostatic interactions between the ionizable amine groups of the drugs and the anionic carboxylate groups of the polysaccharides. This, in turn, results in a close proximity of the drugs to the polysaccharide chain, where the water molecules have a lower mobility and, therefore, a lower thermodynamic activity.

PMID:36889417 | DOI:10.1016/j.ijpharm.2023.122798

Crit Rev Microbiol. 2023 Mar 8:1-18. doi: 10.1080/1040841X.2023.2186215. Online ahead of print.

ABSTRACT

The widespread antimicrobial resistance (AMR) calls for the development of new antimicrobial strategies. Antibiotic adjuvant rescues antibiotic activity and increases the life span of the antibiotics, representing a more productive, timely, and cost-effective strategy in fighting drug-resistant pathogens. Antimicrobial peptides (AMPs) from synthetic and natural sources are considered new-generation antibacterial agents. Besides their direct antimicrobial activity, growing evidence shows that some AMPs effectively enhance the activity of conventional antibiotics. The combinations of AMPs and antibiotics display an improved therapeutic effect on antibiotic-resistant bacterial infections and minimize the emergence of resistance. In this review, we discuss the value of AMPs in the age of resistance, including modes of action, limiting evolutionary resistance, and their designing strategies. We summarise the recent advances in combining AMPs and antibiotics against antibiotic-resistant pathogens, as well as their synergistic mechanisms. Lastly, we highlight the challenges and opportunities associated with the use of AMPs as potential antibiotic adjuvants. This will shed new light on the deployment of synergistic combinations to address the AMR crisis.

PMID:36890767 | DOI:10.1080/1040841X.2023.2186215

J Am Chem Soc. 2023 Mar 22;145(11):6067-6078. doi: 10.1021/jacs.2c10655. Epub 2023 Mar 7.

ABSTRACT

Described are ligand-directed catalysts for live-cell, photocatalytic activation of bioorthogonal chemistry. Catalytic groups are localized via a tethered ligand either to DNA or to tubulin, and red light (660 nm) photocatalysis is used to initiate a cascade of DHTz oxidation, intramolecular Diels-Alder reaction, and elimination to release phenolic compounds. Silarhodamine (SiR) dyes, more conventionally used as biological fluorophores, serve as photocatalysts that have high cytocompatibility and produce minimal singlet oxygen. Commercially available conjugates of Hoechst dye (SiR-H) and docetaxel (SiR-T) are used to localize SiR to the nucleus and microtubules, respectively. Computation was used to assist the design of a new class of redox-activated photocage to release either phenol or n-CA4, a microtubule-destabilizing agent. In model studies, uncaging is complete within 5 min using only 2 μM SiR and 40 μM photocage. In situ spectroscopic studies support a mechanism involving rapid intramolecular Diels-Alder reaction and a rate-determining elimination step. In cellular studies, this uncaging process is successful at low concentrations of both the photocage (25 nM) and the SiR-H dye (500 nM). Uncaging n-CA4 causes microtubule depolymerization and an accompanying reduction in cell area. Control studies demonstrate that SiR-H catalyzes uncaging inside the cell, and not in the extracellular environment. With SiR-T, the same dye serves as a photocatalyst and the fluorescent reporter for microtubule depolymerization, and with confocal microscopy, it was possible to visualize microtubule depolymerization in real time as the result of photocatalytic uncaging in live cells.

PMID:36881718 | PMC:PMC10589873 | DOI:10.1021/jacs.2c10655

Proc Natl Acad Sci U S A. 2023 Mar 14;120(11):e2220012120. doi: 10.1073/pnas.2220012120. Epub 2023 Mar 9.

ABSTRACT

Adenosine triphosphate-binding cassette (ABC) transporters, such as multidrug resistance protein 1 (MRP1), protect against cellular toxicity by exporting xenobiotic compounds across the plasma membrane. However, constitutive MRP1 function hinders drug delivery across the blood-brain barrier, and MRP1 overexpression in certain cancers leads to acquired multidrug resistance and chemotherapy failure. Small-molecule inhibitors have the potential to block substrate transport, but few show specificity for MRP1. Here we identify a macrocyclic peptide, named CPI1, which inhibits MRP1 with nanomolar potency but shows minimal inhibition of a related multidrug transporter P-glycoprotein. A cryoelectron microscopy (cryo-EM) structure at 3.27 Å resolution shows that CPI1 binds MRP1 at the same location as the physiological substrate leukotriene C4 (LTC₄). Residues that interact with both ligands contain large, flexible sidechains that can form a variety of interactions, revealing how MRP1 recognizes multiple structurally unrelated molecules. CPI1 binding prevents the conformational changes necessary for adenosine triphosphate (ATP) hydrolysis and substrate transport, suggesting it may have potential as a therapeutic candidate.

PMID:36893260 | PMC:PMC10089224 | DOI:10.1073/pnas.2220012120

Nat Commun. 2023 Mar 2;14(1):1183. doi: 10.1038/s41467-023-36882-6.

ABSTRACT

Candida glabrata is a major fungal pathogen notable for causing recalcitrant infections, rapid emergence of drug-resistant strains, and its ability to survive and proliferate within macrophages. Resembling bacterial persisters, a subset of genetically drug-susceptible C. glabrata cells can survive lethal exposure to the fungicidal echinocandin drugs. Herein, we show that macrophage internalization induces cidal drug tolerance in C. glabrata, expanding the persister reservoir from which echinocandin-resistant mutants emerge. We show that this drug tolerance is associated with non-proliferation and is triggered by macrophage-induced oxidative stress, and that deletion of genes involved in reactive oxygen species detoxification significantly increases the emergence of echinocandin-resistant mutants. Finally, we show that the fungicidal drug amphotericin B can kill intracellular C. glabrata echinocandin persisters, reducing emergence of resistance. Our study supports the hypothesis that intra-macrophage C. glabrata is a reservoir of recalcitrant/drug-resistant infections, and that drug alternating strategies can be developed to eliminate this reservoir.

PMID:36864040 | PMC:PMC9981703 | DOI:10.1038/s41467-023-36882-6

Commun Chem. 2023 Mar 4;6(1):48. doi: 10.1038/s42004-023-00841-5.

ABSTRACT

Macrocyclisation of proteins and peptides results in a remarkable increase in structural stability, making cyclic peptides and proteins of great interest in drug discovery-either directly as drug leads or as in the case of cyclised nanodiscs (cNDs), as tools for studies of trans-membrane receptors and membrane-active peptides. Various biological methods have been developed that are capable of yielding head-to-tail macrocyclised products. Recent advances in enzyme-catalysed macrocyclisation include discovery of new enzymes or design of new engineered enzymes. Here, we describe the engineering of a self-cyclising "autocyclase" protein, capable of performing a controllable unimolecular reaction for generation of cyclic biomolecules in high yield. We characterise the self-cyclisation reaction mechanism, and demonstrate how the unimolecular reaction path provides alternative avenues for addressing existing challenges in enzymatic cyclisation. We use the method to produce several notable cyclic peptides and proteins, demonstrating how autocyclases offer a simple, alternative way to access a vast diversity of macrocyclic biomolecules.

PMID:36871076 | PMC:PMC9985607 | DOI:10.1038/s42004-023-00841-5

Nature. 2023 Mar;615(7951):300-304. doi: 10.1038/s41586-023-05750-0. Epub 2023 Mar 1.

ABSTRACT

Gram-negative bacteria surround their cytoplasmic membrane with a peptidoglycan (PG) cell wall and an outer membrane (OM) with an outer leaflet composed of lipopolysaccharide (LPS)¹. This complex envelope presents a formidable barrier to drug entry and is a major determinant of the intrinsic antibiotic resistance of these organisms². The biogenesis pathways that build the surface are also targets of many of our most effective antibacterial therapies³. Understanding the molecular mechanisms underlying the assembly of the Gram-negative envelope therefore promises to aid the development of new treatments effective against the growing problem of drug-resistant infections. Although the individual pathways for PG and OM synthesis and assembly are well characterized, almost nothing is known about how the biogenesis of these essential surface layers is coordinated. Here we report the discovery of a regulatory interaction between the committed enzymes for the PG and LPS synthesis pathways in the Gram-negative pathogen Pseudomonas aeruginosa. We show that the PG synthesis enzyme MurA interacts directly and specifically with the LPS synthesis enzyme LpxC. Moreover, MurA was shown to stimulate LpxC activity in cells and in a purified system. Our results support a model in which the assembly of the PG and OM layers in many proteobacterial species is coordinated by linking the activities of the committed enzymes in their respective synthesis pathways.

PMID:36859542 | PMC:PMC9995270 | DOI:10.1038/s41586-023-05750-0

PNAS Nexus. 2023 Jan 27;2(2):pgad017. doi: 10.1093/pnasnexus/pgad017. eCollection 2023 Feb.

ABSTRACT

Ehrlichia chaffeensis is an obligatory intracellular bacterium that infects monocytes and macrophages, and causes human monocytic ehrlichiosis, an emerging life-threatening infectious disease. Ehrlichia translocated factor-1 (Etf-1), a type IV secretion system effector, is essential for Ehrlichia infection of host cells. Etf-1 translocates to mitochondria to block host apoptosis; furthermore, it can bind Beclin 1 (ATG6) to induce cellular autophagy and localize to E. chaffeensis-inclusion membrane to obtain host-cell cytoplasmic nutrients. In this study, we screened a synthetic library of over 320,000 cell-permeable macrocyclic peptides, which consist of an ensemble of random peptide sequences in the first ring and a small family of cell-penetrating peptides in the second ring, for Etf-1 binding. Library screening followed by hit optimization identified multiple Etf-1-binding peptides (with K _D values of 1-10 μM) that efficiently enter the cytosol of mammalian cells. Peptides B7, C8, B7-131-5, B7-133-3, and B7-133-8 significantly inhibited Ehrlichia infection of THP-1 cells. Mechanistic studies revealed that peptide B7 and its derivatives inhibited the binding of Etf-1 to Beclin 1, and Etf-1 localization to E. chaffeensis-inclusion membranes, but not Etf-1 localization to the mitochondria. Our results not only affirm the critical role of Etf-1 functions in E. chaffeensis infection, but also demonstrate the feasibility of developing macrocyclic peptides as powerful chemical probes and potential treatment of diseases caused by Ehrlichia and other intracellular pathogens.

PMID:36874272 | PMC:PMC9982066 | DOI:10.1093/pnasnexus/pgad017

bioRxiv. 2023 Feb 26:2023.02.25.529956. doi: 10.1101/2023.02.25.529956. Preprint.

ABSTRACT

Deep learning networks offer considerable opportunities for accurate structure prediction and design of biomolecules. While cyclic peptides have gained significant traction as a therapeutic modality, developing deep learning methods for designing such peptides has been slow, mostly due to the small number of available structures for molecules in this size range. Here, we report approaches to modify the AlphaFold network for accurate structure prediction and design of cyclic peptides. Our results show this approach can accurately predict the structures of native cyclic peptides from a single sequence, with 36 out of 49 cases predicted with high confidence (pLDDT > 0.85) matching the native structure with root mean squared deviation (RMSD) less than 1.5 Å. Further extending our approach, we describe computational methods for designing sequences of peptide backbones generated by other backbone sampling methods and for de novo design of new macrocyclic peptides. We extensively sampled the structural diversity of cyclic peptides between 7-13 amino acids, and identified around 10,000 unique design candidates predicted to fold into the designed structures with high confidence. X-ray crystal structures for seven sequences with diverse sizes and structures designed by our approach match very closely with the design models (root mean squared deviation < 1.0 Å), highlighting the atomic level accuracy in our approach. The computational methods and scaffolds developed here provide the basis for custom-designing peptides for targeted therapeutic applications.

PMID:36865323 | PMC:PMC9980166 | DOI:10.1101/2023.02.25.529956

Brief Bioinform. 2023 Mar 19;24(2):bbad058. doi: 10.1093/bib/bbad058.

ABSTRACT

With the emergence of multidrug-resistant bacteria, antimicrobial peptides (AMPs) offer promising options for replacing traditional antibiotics to treat bacterial infections, but discovering and designing AMPs using traditional methods is a time-consuming and costly process. Deep learning has been applied to the de novo design of AMPs and address AMP classification with high efficiency. In this study, several natural language processing models were combined to design and identify AMPs, i.e. sequence generative adversarial nets, bidirectional encoder representations from transformers and multilayer perceptron. Then, six candidate AMPs were screened by AlphaFold2 structure prediction and molecular dynamic simulations. These peptides show low homology with known AMPs and belong to a novel class of AMPs. After initial bioactivity testing, one of the peptides, A-222, showed inhibition against gram-positive and gram-negative bacteria. The structural analysis of this novel peptide A-222 obtained by nuclear magnetic resonance confirmed the presence of an alpha-helix, which was consistent with the results predicted by AlphaFold2. We then performed a structure-activity relationship study to design a new series of peptide analogs and found that the activities of these analogs could be increased by 4-8-fold against Stenotrophomonas maltophilia WH 006 and Pseudomonas aeruginosa PAO1. Overall, deep learning shows great potential in accelerating the discovery of novel AMPs and holds promise as an important tool for developing novel AMPs.

PMID:36857616 | DOI:10.1093/bib/bbad058

J Pept Sci. 2023 Feb 26:e3486. doi: 10.1002/psc.3486. Online ahead of print.

ABSTRACT

Receptor-derived peptides have played an important role in elucidating chemokine-receptor interactions. For the inflammatory chemokine CXCL8, a site II-mimetic peptide has been derived from parts of extracellular loops 2 and 3 and adjacent transmembrane helices of its receptor CXCR1 (Helmer et al., RSC Adv., 2015, 5, 25657). The peptide sequence with a C-terminal glutamine did not bind to CXCL8, whereas one with a C-terminal glutamate did but with low micromolar affinity. We sought to improve the affinity and protease stability of the latter peptide through cyclization whilst also cyclizing the former for control purposes. To identify a cyclization strategy that permits a receptor-like interaction, we conducted a molecular dynamics (MD) simulation of CXCL8 in complex with full-length CXCR1. We introduced a linker to provide an appropriate spacing between the termini and used an on-resin side chain-to-tail cyclization strategy. Upon chemokine binding, the fluorescence intensity of the tetramethylrhodamine (TAMRA)-labeled cyclic peptides increased while the fluorescence anisotropy decreased. Additional MD simulations indicated that the fluorophore interacts with the peptide macrocycle so that chemokine binding leads to its displacement and observed changes in fluorescence. Macrocyclization of both 18-amino acid-long peptides led to the same low micromolar affinity for CXCL8. Likewise, both TAMRA-labeled linear peptides interacted with CXCL8 with similar affinities. Interestingly, the linear TAMRA-labeled peptides were more resistant to tryptic digestion than the unlabeled counterparts, whereas the cyclized peptides were not degraded at all. We conclude that the TAMRA fluorophore tends to interact with peptides altering their protease stability and behavior in fluorescence-based assays.

PMID:36843216 | DOI:10.1002/psc.3486

mBio. 2023 Feb 21:e0021723. doi: 10.1128/mbio.00217-23. Online ahead of print.

ABSTRACT

Phazolicin (PHZ) is a peptide antibiotic exhibiting narrow-spectrum activity against rhizobia closely related to its producer, Rhizobium sp. strain Pop5. Here, we show that the frequency of spontaneous PHZ-resistant mutants in Sinorhizobium meliloti is below the detection limit. We find that PHZ can enter S. meliloti cells through two distinct promiscuous peptide transporters, BacA and YejABEF, which belong to the SLiPT (SbmA-like peptide transporter) and ABC (ATP-binding cassette) transporter families, respectively. The dual-uptake mode explains the lack of observed resistance acquisition because the simultaneous inactivation of both transporters is necessary for resistance to PHZ. Since both BacA and YejABEF are essential for the development of functional symbiosis of S. meliloti with leguminous plants, the unlikely acquisition of PHZ resistance via the inactivation of these transporters is further disfavored. A whole-genome transposon sequencing screen did not reveal additional genes that can provide strong PHZ resistance when inactivated. However, it was found that the capsular polysaccharide KPS, the novel putative envelope polysaccharide PPP (PHZ-protecting polysaccharide), as well as the peptidoglycan layer jointly contribute to the sensitivity of S. meliloti to PHZ, most likely serving as barriers that reduce the amount of PHZ transported inside the cell. IMPORTANCE Many bacteria produce antimicrobial peptides to eliminate competitors and create an exclusive niche. These peptides act either by membrane disruption or by inhibiting essential intracellular processes. The Achilles' heel of the latter type of antimicrobials is their dependence on transporters to enter susceptible cells. Transporter inactivation results in resistance. Here, we show that a rhizobial ribosome-targeting peptide, phazolicin (PHZ), uses two different transporters, BacA and YejABEF, to enter the cells of a symbiotic bacterium, Sinorhizobium meliloti. This dual-entry mode dramatically reduces the probability of the appearance of PHZ-resistant mutants. Since these transporters are also crucial for S. meliloti symbiotic associations with host plants, their inactivation in natural settings is strongly disfavored, making PHZ an attractive lead for the development of biocontrol agents for agriculture.

PMID:36802165 | DOI:10.1128/mbio.00217-23