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Microbiology and Molecular Biology... Jun 2023Clinical management of Staphylococcus aureus infections presents a challenge due to the high incidence, considerable virulence, and emergence of drug resistance... (Review)
Review
Clinical management of Staphylococcus aureus infections presents a challenge due to the high incidence, considerable virulence, and emergence of drug resistance mechanisms. The treatment of drug-resistant strains, such as methicillin-resistant S. aureus (MRSA), is further complicated by the development of tolerance and persistence to antimicrobial agents in clinical use. To address these challenges, membrane disruptors, that are not generally considered during drug discovery for agents against S. aureus, should be explored. The cell membrane protects S. aureus from external stresses and antimicrobial agents, but membrane-targeting antimicrobial agents are probably less likely to promote bacterial resistance. Nontypical linear cationic antimicrobial peptides (AMPs), highly modified AMPs such as daptomycin (lipopeptide), bacitracin (cyclic peptide), and gramicidin S (cyclic peptide), are currently in clinical use. Recent studies have demonstrated that AMPs and small molecules can penetrate the cell membrane of S. aureus, inhibit phospholipid biosynthesis, or block the passage of solutes between the periplasm and the exterior of the cell. In addition to their primary mechanism of action (MOA) that targets the bacterial membrane, AMPs and small molecules may also impact bacteria through secondary mechanisms such as targeting the biofilm, and downregulating virulence genes of S. aureus. In this review, we discuss the current state of research into cell membrane-targeting AMPs and small molecules and their potential mechanisms of action against drug-resistant physiological forms of S. aureus, including persister cells and biofilms.
Topics: Humans; Staphylococcus aureus; Anti-Bacterial Agents; Methicillin-Resistant Staphylococcus aureus; Antimicrobial Peptides; Anti-Infective Agents; Peptides, Cyclic; Cell Membrane; Biofilms; Staphylococcal Infections
PubMed: 37129495
DOI: 10.1128/mmbr.00037-22 -
Synthetic and Systems Biotechnology Jun 2023Microorganisms are important sources of various natural products that have been commercialized for human medicine and animal healthcare. Bacitracin is an important... (Review)
Review
Microorganisms are important sources of various natural products that have been commercialized for human medicine and animal healthcare. Bacitracin is an important antibacterial natural product predominantly produced by and , and it is characterized by a broad antimicrobial spectrum, strong activity and low resistance, thus bacitracin is extensively applied in animal feed and veterinary medicine industries. In recent years, various strategies have been proposed to improve bacitracin production. Herein, we systematically describe the regulation of bacitracin biosynthesis in genus and its associated mechanism, to provide a theoretical basis for bacitracin overproduction. The metabolic engineering strategies applied for bacitracin production are explored, including improving substrate utilization, using an enlarged precursor amino acid pool, increasing ATP supply and NADPH generation, and engineering transcription regulators. We also present several approaches of fermentation process optimization to facilitate the industrial large-scale production of bacitracin. Finally, the challenges and prospects associated with microbial bacitracin synthesis are discussed to facilitate the establishment of high-yield and low-cost biological factories.
PubMed: 37122958
DOI: 10.1016/j.synbio.2023.03.009 -
Frontiers in Immunology 2022Allergic drug reaction or drug allergy is an immunologically mediated drug hypersensitivity reaction (DHR). G-protein coupled receptors (GPCRs) are common drug targets...
BACKGROUND
Allergic drug reaction or drug allergy is an immunologically mediated drug hypersensitivity reaction (DHR). G-protein coupled receptors (GPCRs) are common drug targets and communicate extracellular signals that initiate cellular responses. Recent evidence shows that GPCR MRGPRX2 is of major importance in IgE-independent pseudo-allergic DHRs based on the suspected interactions between many FDA-approved peptidergic compounds and MRGPRX2.
OBJECTIVE
Our aim was to uncover novel MRGPRX2-selective and -potent agonists as drug candidates responsible for clinical features of pseudo-allergic DHRs.
METHODS
We conducted a primary high-throughput screening (HTS), coupled with mutagenesis targeting the MRGPRX2 N62S mutation, on a panel of 3,456 library compounds. We discovered pharmacologically active hit compounds as agonists of the MRGPRX2 protein according to high degrees of potency evaluated by the calcium response and validated by the degranulation assay. Using the molecular tool Forge, we also characterized the structure-activity relationship shared by identified hit compounds.
RESULTS
The alternative allele of single nucleotide polymorphism rs10833049 (N62S) in MRGPRX2 demonstrated property in response to substance P and antineoplastic agent daunorubicin hydrochloride. We applied a unique assay system targeting the N62S mutation to the HTS and identified 84 MRGPRX2-selective active hit compounds representing diverse classes according to primary drug indications. The top five highly represented groups included fluoroquinolone and non-fluoroquinolone antibiotics; antidepressive/antipsychotic; antihistaminic and antineoplastic agents. We classified hit compounds into 14 clusters representing a variety of chemical and drug classes beyond those reported, such as opioids, neuromuscular blocking agents, and fluoroquinolones. We further demonstrated MRGPRX2-dependent degranulation in the human mast cell line LAD2 cells induced by three novel agonists representing the non-fluoroquinolone antibiotics (bacitracin A), anti-allergic agents (brompheniramine maleate) and tyrosine-kinase inhibitors (imatinib mesylate).
CONCLUSION
Our findings could facilitate the development of interventions for personalized prevention and treatment of DHRs, as well as future pharmacogenetic investigations of MRGPRX2 in relevant disease cohorts.
Topics: Humans; Receptors, Neuropeptide; Cell Degranulation; Mast Cells; Nerve Tissue Proteins; Receptors, G-Protein-Coupled; Drug Hypersensitivity; Anti-Bacterial Agents
PubMed: 36341461
DOI: 10.3389/fimmu.2022.997389 -
Poultry Science Jan 2022Woody breast (WB) is a myopathy that is related to the increasing growth rate. Understanding the influence of management factors on WB formation and development is...
Woody breast (WB) is a myopathy that is related to the increasing growth rate. Understanding the influence of management factors on WB formation and development is important to minimize WB. This study was conducted to define how management factors affect broiler growth performance, processing yield, and WB incidence. Ross × Ross 708 chicks were randomly assigned to a 3 (diet) × 2 (cocci challenge) × 2 (sex) factorial arrangement of treatments. The 3 dietary treatments were: control diet (corn-soybean meal basal diet), antibiotic diet (basal diet + 6.075 mg bacitracin /kg feed), and probiotic diet (basal diet + 2.2 × 10 CFU Bacillus subtilis PB6/kg feed). Birds in cocci challenge treatments received 20 × live cocci vaccine on d 14. The hardness of breast muscle in live birds was determined by palpation and grouped into Normal, Slight, Moderate, and Severe categories. Across diet and sex treatments, the cocci challenge resulted in decreases in body weight (BW) on d 29 and 35 (P < 0.0001 and = 0.032) in body weight gain (BWG) from d 14 to 29 (P < 0.0001). However, an increase of BW occurred on d 35 (P = 0.032) and an increase of BWG occurred from d 29 to 35 and d 35 to 43 (P = 0.0001 and 0.002), and the cocci challenge increased WB incidence on d 29 (P = 0.043) and d 43 (P = 0.013). Across challenge and sex treatments, birds fed the antibiotic diet exhibited a higher growth rate (GR) than those fed the control or probiotic diet from d 0 to 14 (P = 0.016), but not after d 14 (P > 0.05). Across sex, the antibiotic and probiotic diets increased WB incidence for those birds that did not receive a cocci challenge on d 43 (P = 0.040). Across challenge and diet treatments, males exhibited a higher BW, BWG, and GR throughout all growth phases, and males showed a higher WB incidence on d 29, 35, and 43 (P = 0.002, P < 0.0001, and P = 0.0002, respectively). In conclusion, bacitracin and Eimeria spp. increased WB incidence, BW, and GR. However, Bacillus subtilis increased WB incidence in male broilers without affecting BW and GR.
Topics: Animals; Bacillus subtilis; Bacitracin; Chickens; Eimeria; Incidence; Male; Muscular Diseases
PubMed: 34788711
DOI: 10.1016/j.psj.2021.101512 -
International Journal of Molecular... Aug 2022The effect of Bacitracin as an antibiotic acting against Gram-positive bacterial cells was evaluated in combination with hexahistidine-containing organophosphate...
The effect of Bacitracin as an antibiotic acting against Gram-positive bacterial cells was evaluated in combination with hexahistidine-containing organophosphate hydrolase (His-OPH), possessing lactonase activity against various -acylhomoserine lactones produced by most Gram-negative bacteria as quorum-sensing molecules. The molecular docking technique was used to obtain in silico confirmation of possible interactions between molecules of His-OPH and Bacitracin as well as the absence of a significant influence of such interactions on the enzymatic catalysis. The in vitro experiments showed a sufficient catalytic efficiency of action of the His-OPH/Bacitracin combination as compared to the native enzyme. The notable improvement (up to 3.3 times) of antibacterial efficiency of Bacitracin was revealed in relation to Gram-negative bacteria when it was used in combination with His-OPH. For the first time, the action of the Bacitracin with and without His-OPH was shown to be effective against various yeast strains, and the presence of the enzyme increased the antibiotic effect up to 8.5 times. To estimate the role of the enzyme in the success of His-OPH/Bacitracin with yeast, in silico experiments (molecular docking) with various fungous lactone-containing molecules were undertaken, and the opportunity of their enzymatic hydrolysis by His-OPH was revealed in the presence and absence of Bacitracin.
Topics: Acyl-Butyrolactones; Anti-Bacterial Agents; Bacitracin; Molecular Docking Simulation; Saccharomyces cerevisiae
PubMed: 36012663
DOI: 10.3390/ijms23169400 -
International Journal of Cardiology.... Jun 2021Antibiotic envelopes are being developed for cardiac implantable electronic device (CIED) wrapping to reduce the risk of infections.
INTRODUCTION
Antibiotic envelopes are being developed for cardiac implantable electronic device (CIED) wrapping to reduce the risk of infections.
METHODS
Fifteen CIED infection-associated bacterial isolates of and were used to assess biofilm formation on Hylomate® compared to titanium, silicone and polyurethane coupons pre-treated with vancomycin (400 µg/ml), bacitracin (1000 U/ml) or a combination of rifampin (80 µg/ml) plus minocycline (50 µg/ml). Scanning electron microscopy (SEM) was performed to visualize bacteria on Hylomate®.
RESULTS
There was significantly less (p < 0.05) and on Hylomate® pre-treated with vancomycin, bacitracin or rifampin plus minocycline after 24 h of incubation (≤1.00 log CFU/cm) compared with titanium, silicone or polyurethane pre-treated with vancomycin, bacitracin or rifampin plus minocycline. . biofilms were not detected (≤1.00 log CFU/cm) on pre-treated Hylomate® coupons.
CONCLUSIONS
This study showed that Hylomate® coupons pre-treated with antibiotics reduced staphylococcal and biofilm formation
PubMed: 34159252
DOI: 10.1016/j.ijcha.2021.100801 -
Poultry Science Dec 2022Nutritional additives such as propolis seek to improve intestinal health as an alternative to the global ban on in-feed antibiotics used as growth promoters (AGP). The...
Nutritional additives such as propolis seek to improve intestinal health as an alternative to the global ban on in-feed antibiotics used as growth promoters (AGP). The objective of this study was to evaluate the effect of propolis supplementation in diet of broilers. Four hundred and fifty straight-run Ross 308 AP broilers were fed with a basal diet (BD) throughout the whole experimental period. Birds were randomly distributed into 5 groups at d 14: negative control without antibiotics nor propolis (AGP-), positive control 500 ppm of Zinc Bacitracin as growth promoter (AGP+), and 3 groups supplemented with 150, 300, and 450 ppm of propolis. Every group included 6 replicates of 15 birds each. Propolis concentration was increased from d 22 to 42, in experimental groups to 300, 600, and 900 ppm of propolis, and 10% of raw soybean was included as a challenge in all groups during the same period. Analysis of productive parameters, intestinal morphometry, and relative quantification of genes associated with epithelial integrity by qPCR were performed at 21 and 42 d. The groups with the greatest weights were those that consumed diets including 150 (21 d) and 900 ppm (42 d) of propolis compared with all treatments. The lowest score of ISI was found at 300 (21 d) and 600 ppm (42 d). A lower degree of injury in digestive system was seen with the inclusion of 300 ppm (21 d) and 900 ppm (42 d). Up-regulation of zonula occludens-1 (ZO-1) was observed in jejunum of broilers supplemented with 150 and 300 ppm at 21 d. Up-regulation of ZO-1 and TGF-β was also evidenced in ileum at all propolis inclusion levels at 42-day-old compared to AGP+ and AGP-. The beneficial effects were evidenced at inclusion levels of 150 ppm in the starter and 900 ppm in the finisher. According to the results, the Colombian propolis inclusion can improve productive performance, physiological parameters, and gene expression associated with intestinal integrity.
Topics: Animals; Animal Feed; Anti-Bacterial Agents; Chickens; Colombia; Diet; Dietary Supplements; Propolis
PubMed: 36279608
DOI: 10.1016/j.psj.2022.102159 -
Proceedings of the National Academy of... Apr 2022SignificanceMany gram-positive organisms have evolved an elegant solution to sense and resist antimicrobial peptides that inhibit cell-wall synthesis. These organisms...
SignificanceMany gram-positive organisms have evolved an elegant solution to sense and resist antimicrobial peptides that inhibit cell-wall synthesis. These organisms express an unusual "Bce-type" adenosine triphosphate-binding cassette (ABC) transporter that recognizes complexes formed between antimicrobial peptides and lipids involved in cell-wall biosynthesis. In this work, we provide the first structural snapshots of a Bce-type ABC transporter trapped in different conformational states. Our structures and associated biochemical data provide key insights into the novel target protection mechanism that these unusual ABC transporters use to sense and resist antimicrobial peptides. The studies described herein set the stage to begin developing a comprehensive molecular understanding of the diverse interactions between antimicrobial peptides and conserved resistance machinery found across most gram-positive organisms.
Topics: ATP-Binding Cassette Transporters; Anti-Bacterial Agents; Bacillus subtilis; Bacitracin; Bacterial Proteins; Drug Resistance, Bacterial; Gene Expression Regulation, Bacterial; Membrane Transport Proteins
PubMed: 35349335
DOI: 10.1073/pnas.2123268119 -
The Journal of Physical Chemistry... Apr 2024Terahertz time-domain spectroscopy and differential scanning calorimetry were used to study the role of the dynamics of biomolecules decoupled from solvent effects....
Terahertz time-domain spectroscopy and differential scanning calorimetry were used to study the role of the dynamics of biomolecules decoupled from solvent effects. Lyophilized sucrose exhibited steadily increasing absorption with temperature as anharmonic excitations commenced as the system emerged from a deep minimum of the potential energy landscape where harmonic vibrations dominate. The polypeptide bacitracin and two globular proteins, lysozyme and human serum albumin, showed a more complex temperature dependence. Further analysis focused on the spectral signature below and above the boson peak. We found evidence of the onset of anharmonic motions that are characteristic for partial unfolding and molecular jamming in the dry biomolecules. The activation of modes of the protein molecules at temperatures comparable to the protein dynamical transition temperature was observed in the absence of hydration. No evidence of Fröhlich coherence, postulated to facilitate biological function, was found in our experiments.
Topics: Humans; Proteins; Solvents; Temperature; Water
PubMed: 38527099
DOI: 10.1021/acs.jpclett.3c03584