Brianna Dalesandro

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Porin loss in Klebsiella pneumoniae clinical isolates impacts production of virulence factors and survival within macrophages.

Int J Med Microbiol. 2019 Apr 16;:

Authors: Brunson DN, Maldosevic E, Velez A, Figgins E, Ellis TN

Abstract
Clinical isolates of Klebsiella pneumoniae are often resistant to beta-lactam antibiotics via the acquisition of extended spectrum beta lactamase (ESBL) enzymes paired with loss of one or both major outer membrane porins. It has been well established that loss of OmpK35 and/or OmpK36 correlates with increased minimum inhibitory concentrations of antibiotics that target the peptidoglycan. However, little is known concerning the downstream effects porin loss might have on other major virulence factors such as the polysaccharide capsule or LPS. Furthermore, it is unknown whether these cumulative changes impact pathogenesis. Therefore, the focus of this study was to identify alterations in production of the major virulence factors due to porin loss; and to investigate the effect these changes have on host pathogen interactions. Our data demonstrates that loss of a single porin is paired with reductions in capsule, increased LPS content, and up-regulated transcription of compensatory porin genes. In contrast, loss of both porins resulted in a significant increase in capsule production. Loss of OmpK35 alone or dual porin loss was further associated with reduced oxidative burst by macrophages and increased ability of the bacteria to survive phagocytic killing. These data indicate that porin loss is accompanied by a suite of changes in other virulence-associated factors. These cumulative changes act to nullify any negative fitness effect due to lack of the nonspecific porin proteins, allowing the bacteria to grow and survive phagocytic immune responses.

PMID: 31010630 [PubMed - as supplied by publisher]

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Protection against Tetanus and Diphtheria in Europe: The impact of age, gender and country of origin based on data from the MARK-AGE Study.

Exp Gerontol. 2018 05;105:109-112

Authors: Weinberger B, Keller M, Putzer C, Breitenberger D, Koller B, Fiegl S, Moreno-Villanueva M, Bernhardt J, Franceschi C, Voutetakis K, Gonos ES, Hurme M, Sikora E, Toussaint O, Debacq-Chainiaux F, Grune T, Breusing N, Bürkle A, Grubeck-Loebenstein B

Abstract
Due to the successful implementation of vaccination strategies early-life morbidity and mortality due to infectious disease has been reduced dramatically. Vaccines against tetanus and diphtheria are among the most frequently used vaccines worldwide, but various studies in different European countries have shown that protection against tetanus and particularly against diphtheria is unsatisfactory in adults and older persons. In this study we analyzed tetanus- and diphtheria-specific antibody concentrations in 2100 adults of different age from 6 selected European countries (Austria, Belgium, Germany, Greece, Italy, Poland) in order to investigate differences in the level of protection against tetanus and diphtheria across Europe. Our data reveal that tetanus- and diphtheria-specific antibody concentrations vary greatly between countries, which is also reflected in the percentage of persons with antibody concentrations below the protective level (0.1IU/ml), which ranged from 2 to 31% percent for tetanus and 28-63% for diphtheria. In most countries, tetanus- and diphtheria-specific antibody concentrations decrease with age. This phenomenon is more pronounced in countries with generally low antibody levels, such as Italy, Poland and Greece. Interestingly, tetanus-specific antibody concentrations are generally higher in males than in females, which is probably due to vaccination during their military service or more frequent booster vaccinations after injuries, whereas no gender-related differences were found for diphtheria-specific antibodies. In conclusion, our study demonstrates that the European population is not fully protected against tetanus and diphtheria. Measures to improve protection should include a life-long perspective on vaccination, more education to increase awareness of and compliance with vaccination guidelines, and a harmonization of recommendations and incentives across Europe.

PMID: 29017961 [PubMed - indexed for MEDLINE]

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Antibodies to vaccine antigens in pooled polyclonal human IgG products.

Transfusion. 2018 12;58 Suppl 3:3096-3105

Authors: Berger M

Abstract
Immune-deficient patients depend on the antibodies in pooled human immunoglobulin G (IgG) preparations to remain free from serious infections. The potency of IgG preparations is therefore an ongoing concern. The use of pooled IgG to prevent infection is based on the concept that healthy adults have recovered from infections earlier in life and maintain relatively high antibody titers. In general, vaccine-induced immunity is less robust or long-lasting than immunity after natural infection, and many infectious diseases which were formerly widely prevalent have become much less common due to improved hygiene and vaccines. This raises questions as to the adequacy of protective antibodies in current IgG preparations. This paper reviews available data on antibodies against selected bacterial and virus vaccine antigens in current IgG products. Most products contain sufficient antibody to yield levels above minimal protective concentrations to a broad range of pathogens and toxins. Illustrative examples of effects of vaccines on antibody content of IgG products are also discussed: antibody titers to hepatitis A virus in donor plasma pools in both the US and EU are dropping due to decreased natural infection, but they are still sufficient to provide robust protection. Increasing seroprevalence of hepatitis B virus as a result of immunization suggests that antibody titers against this virus may actually be increasing. Finally, serial studies suggest that pooled IgG provides protection against seasonal influenza viruses despite year-to-year antigenic drift, and is also likely to provide at least some protective antibody against potentially pandemic strains.

PMID: 30536430 [PubMed - indexed for MEDLINE]

by Keenan A. Lacey, Michelle E. Mulcahy, Aisling M. Towell, Joan A. Geoghegan, Rachel M. McLoughlin

Staphylococcus aureus expresses a number of cell wall-anchored proteins that mediate adhesion and invasion of host cells and tissues and promote immune evasion, consequently contributing to the virulence of this organism. The cell wall-anchored protein clumping factor B (ClfB) has previously been shown to facilitate S. aureus nasal colonization through high affinity interactions with the cornified envelope in the anterior nares. However, the role of ClfB during skin and soft tissue infection (SSTI) has never been investigated. This study reveals a novel role for ClfB during SSTIs. ClfB is crucial in determining the abscess structure and bacterial burden early in infection and this is dependent upon a specific interaction with the ligand loricrin which is expressed within the abscess tissue. Targeting ClfB using a model vaccine that induced both protective humoral and cellular responses, leads to protection during S. aureus skin infection. This study therefore identifies ClfB as an important antigen for future SSTI vaccines.

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Vitamin D Compounds Are Bactericidal against Streptococcus mutans and Target the Bacitracin-Associated Efflux System.

Antimicrob Agents Chemother. 2018 01;62(1):

Authors: Saputo S, Faustoferri RC, Quivey RG

Abstract
Vitamin D analogs were identified as compounds that induced lysis of planktonic cultures of Streptococcus mutans in a high-throughput screen of FDA-approved drugs. Previous studies have demonstrated that certain derivatives of vitamin D possess lytic activity against other bacteria, though the mechanism has not yet been established. Through the use of a combinatorial approach, the vitamin D derivative doxercalciferol was shown to act synergistically with bacitracin, a polypeptide-type drug that is known to interfere with cell wall synthesis, suggesting that doxercalciferol may act in a bacitracin-related pathway. Innate resistance to bacitracin is attributed to efflux by a conserved ABC-type transporter, which in S. mutans is encoded by the mbrABCD operon. S. mutans possesses two characterized mechanisms of resistance to bacitracin, the ABC transporter, S. mutans bacitracin resistance (Mbr) cassette, consisting of MbrABCD, and the rhamnose-glucose polysaccharide (Rgp) system, RgpABCDEFGHI. Loss of function of the transporter in ΔmbrA and ΔmbrD mutants exacerbated the effect of the combination of doxercalciferol and bacitracin. Despite conservation of a transporter homologous to mbrABCD, the combination of doxercalciferol and bacitracin appeared to be synergistic only in streptococcal species. We conclude that vitamin D derivatives possess lytic activity against S. mutans and act through a mechanism dependent on the bacitracin resistance mechanism of MbrABCD.

PMID: 29061743 [PubMed - indexed for MEDLINE]

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Antimicrobial Peptide JH-3 Effectively Kills Salmonella enterica Serovar Typhimurium Strain CVCC541 and Reduces Its Pathogenicity in Mice.

Probiotics Antimicrob Proteins. 2019 Apr 18;:

Authors: Wang L, Zhao X, Xia X, Zhu C, Qin W, Xu Y, Hang B, Sun Y, Chen S, Zhang H, Jiang J, Hu J, Fotina H, Zhang G

Abstract
Salmonella is an important zoonotic pathogen and is a major cause of gastrointestinal diseases worldwide. The current serious problem of antibiotic abuse has prompted the search for new substitutes for antibiotics. JH-3 is a small antimicrobial peptide with broad-spectrum bactericidal activity. In this study, we showed that JH-3 has good bactericidal activity towards the clinical isolate Salmonella enterica serovar Typhimurium strain CVCC541. The minimum inhibitory concentration (MIC) of JH-3 against this bacterium was determined to be 100 μg/mL, which could decrease the number of CVCC541 cells by 1000-fold in vitro within 5 h. The transmission electron microscopy (TEM) results showed that JH-3 can damage the cell wall and membrane of CVCC541, leading to the leakage of cell contents and subsequent cell death. To measure the bactericidal activity of CVCC541-infected mice were treated intraperitoneally 40 or 10 mg/kg JH-3 at 2 h or 3 days postinfection. Our results showed that treatment with 40 mg/kg JH-3 at 2 h postinfection had the best therapeutic effect and could significantly protect mice from a lethal dose of CVCC541. Furthermore, the clinical symptoms, bacterial burden in blood and organs, and intestinal pathological changes were all decreased and were close to normal. This study examined the therapeutic effect of the antimicrobial peptide JH-3 against S. enterica CVCC541 infection for the first time and determined the therapeutic effect of different JH-3 doses and treatment times, laying the foundation for studies of new antimicrobial agents.

PMID: 31001786 [PubMed - as supplied by publisher]

by Michele D. Kattke, Jason E. Gosschalk, Orlando E. Martinez, Garima Kumar, Robert T. Gale, Duilio Cascio, Michael R. Sawaya, Martin Philips, Eric D. Brown, Robert T. Clubb

Staphylococcus aureus and other bacterial pathogens affix wall teichoic acids (WTAs) to their surface. These highly abundant anionic glycopolymers have critical functions in bacterial physiology and their susceptibility to β-lactam antibiotics. The membrane-associated TagA glycosyltransferase (GT) catalyzes the first-committed step in WTA biosynthesis and is a founding member of the WecB/TagA/CpsF GT family, more than 6,000 enzymes that synthesize a range of extracellular polysaccharides through a poorly understood mechanism. Crystal structures of TagA from T. italicus in its apo- and UDP-bound states reveal a novel GT fold, and coupled with biochemical and cellular data define the mechanism of catalysis. We propose that enzyme activity is regulated by interactions with the bilayer, which trigger a structural change that facilitates proper active site formation and recognition of the enzyme’s lipid-linked substrate. These findings inform upon the molecular basis of WecB/TagA/CpsF activity and could guide the development of new anti-microbial drugs.

Publication date: 18 April 2019

Source: Cell, Volume 177, Issue 3

Author(s): Jason G. Cyster, Christopher D.C. Allen

Crossing barriers: Cell‐penetrating peptide foldamers are equipped with two properties: cell membrane permeability (as cell‐penetrating peptides) and a stable secondary structure (as peptide foldamers). It is anticipated that the high potential of cell‐penetrating peptide foldamers will become major tools for drug‐delivery systems.

Abstract

Highly efficient drug‐delivery tools for membrane‐impermeable compounds, proteins, and nucleic acids in living cells are useful in the fields of chemical biology and drug discovery, and such tools have been widely studied. One strategy in the development of novel drug‐delivery tools is to utilize cell‐penetrating peptide (CPP) foldamers. CPP foldamers are folded oligopeptides that possess cell membrane permeability. In recent decades, a wide variety of CPP foldamers have been reported by many groups. Herein, CPP foldamers are introduced and discussed from the viewpoints of component monomers (amino acids) and their application as drug‐delivery tools.

Finding a needle in a haystack: Multiplexed proteomics allows the quantification of thousands of proteins among multiple samples. Peptides from multiple samples, labeled by isobaric tags, are indistinguishable in the MS1 spectrum, but separately quantifiable in the MS2 spectrum. The current state of various multiplexed proteomics techniques is reviewed and compared with alternative techniques.

Abstract

Over the last few decades, mass spectrometry‐based proteomics has become an increasingly powerful tool that is now able to routinely detect and quantify thousands of proteins. A major advance for global protein quantification was the introduction of isobaric tags, which, in a single experiment, enabled the global quantification of proteins across multiple samples. Herein, these methods are referred to as multiplexed proteomics. The principles, advantages, and drawbacks of various multiplexed proteomics techniques are discussed and compared with alternative approaches. We also discuss how the emerging combination of multiplexing with targeted proteomics might enable the reliable and high‐quality quantification of very low abundance proteins across multiple conditions. Lastly, we suggest that fusing multiplexed proteomics with data‐independent acquisition approaches might enable the comparison of hundreds of different samples without missing values, while maintaining the superb measurement precision and accuracy obtainable with isobaric tag quantification.

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[Seroprevalence of pertussis toxin antibody in Manisa province of Turkey, after six years implementation of acellular pertussis vaccine].

Mikrobiyol Bul. 2018 Apr;52(2):180-189

Authors: Özbek ÖA, Öktem İMA, Hekimoğlu CH, Sekreter Ö, Emek M, Atasoylu G, Açıkgöz A, Demirpençe N, Ceylan A, Baykal ES, Ünal B

Abstract
Vaccination is the most effective way of preventing pertussis disease. Turkey commenced a routine infant immunization program using whole cell (wP) pertussis vaccine in 1968. Immunization accelerated in 1985 after participation of Turkey in the Expanded Programme on Immunization initiated by the World Health Organization. Acellular vaccine (aP) replaced wP in 2008 and a booster was added to age 6 in 2010. The immunization programme was successful in reducing the morbidity rate from 20.58 per 100.000 in 1970 to the lowest level of 0.01 per 100.000 in 2009. However, reduction of vaccine-induced protection and reduced natural boosting of circulating Bordetella pertussis are likely to increase the susceptibility of the population. As a result, morbidity rate increased from 0.09 per 100.000 to 0.41 per 100.000 in 2015 compared to the previous year. The aim of this epidemiological study was to determine the seroprevalence of pertussis toxin (PT) antibodies among healthy people and its association with various social determinants in Manisa province in Turkey, 6 years after aP replaced wP vaccine. The study was conducted as a cross-sectional study with a sample of 1250 people that was randomly selected from the over 2 years of age population in Manisa in 2014. Seroprevalence of PT antibody was determined as the dependent variable of the study. Independent variables of the study were; gender, age, migration in the last 5 years, occupational class, perceived income, house ownership, number of people per room, annually per capita equivalent income. The presence of anti-PT IgG was detected by quantitatively using a commercially available ELISA kit. The antibody levels were categorized into groups according to pertussis infection or vaccination immune response status. The groups consisted of undetectable (< 5 IU/ml), mid-range (5-< 62.5 IU/ml: more than one year previously), high (62.5-< 125: with in 12 months) and very high (≥ 125 IU/ml: with in 6 months) antibody levels. The test results with ≥ 5 IU/ml were defined as seropositive. Level > 100 IU/ml detected among adolescent and adult participants indicated acute or recently recovered pertussis infection. Chi-square test was used to evaluate association between social determinants and pertussis seropositivity. The seroprevalence of the whole study population was 58.1% (95% CI 55.32-60.79) and no association was found with any of the social determinants. The highest seroprevalence was found among 2-9 age group (68.3%) followed by 70-79 age group (63.5%). The lowest seroprevalence was found among 20-29 age group (50.9%) followed by 10-19 age group (51.6%). When seropositivity levels according to ages were compared, it was found that there was a decrease one year after the first vaccination at 2nd, 4th and 6th months and the booster at the 6th year, with a lowest rate (19%) in 11 year-old. The highest seropositivity (77.3%) with a level of >100 IU/ml (13.6%) were detected at age 15 among all adolescent and adult participants. Adding an adolescent booster to immunization schedule and recommendation of vaccine to elderly people should be considered to reduce the incidence of pertussis disease in Turkey.

PMID: 29933735 [PubMed - indexed for MEDLINE]

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Visualizing conformation transitions of the Lipid II flippase MurJ.

Nat Commun. 2019 Apr 15;10(1):1736

Authors: Kuk ACY, Hao A, Guan Z, Lee SY

Abstract
The biosynthesis of many polysaccharides, including bacterial peptidoglycan and eukaryotic N-linked glycans, requires transport of lipid-linked oligosaccharide (LLO) precursors across the membrane by specialized flippases. MurJ is the flippase for the lipid-linked peptidoglycan precursor Lipid II, a key player in bacterial cell wall synthesis, and a target of recently discovered antibacterials. However, the flipping mechanism of LLOs including Lipid II remains poorly understood due to a dearth of structural information. Here we report crystal structures of MurJ captured in inward-closed, inward-open, inward-occluded and outward-facing conformations. Together with mutagenesis studies, we elucidate the conformational transitions in MurJ that mediate lipid flipping, identify the key ion for function, and provide a framework for the development of inhibitors.

PMID: 30988294 [PubMed - in process]

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Discovery of ERD-308 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Estrogen Receptor (ER).

J Med Chem. 2019 Feb 14;62(3):1420-1442

Authors: Hu J, Hu B, Wang M, Xu F, Miao B, Yang CY, Wang M, Liu Z, Hayes DF, Chinnaswamy K, Delproposto J, Stuckey J, Wang S

Abstract
The estrogen receptor (ER) is a validated target for the treatment of estrogen receptor-positive (ER+) breast cancer. Here, we describe the design, synthesis, and extensive structure-activity relationship (SAR) studies of small-molecule ERα degraders based on the proteolysis targeting chimeras (PROTAC) concept. Our efforts have resulted in the discovery of highly potent and effective PROTAC ER degraders, as exemplified by ERD-308 (32). ERD-308 achieves DC50 (concentration causing 50% of protein degradation) values of 0.17 and 0.43 nM in MCF-7 and T47D ER+ breast cancer cell lines, respectively, and induces >95% of ER degradation at concentrations as low as 5 nM in both cell lines. Significantly, ERD-308 induces more complete ER degradation than fulvestrant, the only approved selective ER degrader (SERD), and is more effective in inhibition of cell proliferation than fulvestrant in MCF-7 cells. Further optimization of ERD-308 may lead to a new therapy for advanced ER+ breast cancer.

PMID: 30990042 [PubMed - in process]

E. coli rolls the dice

<i>E. coli</i> rolls the dice, Published online: 16 April 2019; doi:10.1038/s41579-019-0202-9

This study shows that a subpopulation of bacteria assumes a hypermutable phenotype during antibiotic treatment, which accelerates resistance development.

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Activated Mesenchymal Stem Cells Interact with Antibiotics and Host Innate Immune Responses to Control Chronic Bacterial Infections.

Sci Rep. 2017 08 29;7(1):9575

Authors: Johnson V, Webb T, Norman A, Coy J, Kurihara J, Regan D, Dow S

Abstract
Chronic bacterial infections associated with biofilm formation are often difficult to resolve without extended courses of antibiotic therapy. Mesenchymal stem cells (MSC) exert antibacterial activity in vitro and in acute bacterial infection models, but their activity in chronic infection with biofilm models has not been previously investigated. Therefore, we studied the effects of MSC administration in mouse and dog models of chronic infections associated with biofilms. Mice with chronic Staphylococcus aureus implant infections were treated by i.v. administration of activated or non-activated MSC, with or without antibiotic therapy. The most effective treatment protocol was identified as activated MSC co-administered with antibiotic therapy. Activated MSC were found to accumulate in the wound margins several days after i.v. administration. Macrophages in infected tissues assumed an M2 phenotype, compared to untreated infections which contained predominately M1 macrophages. Bacterial killing by MSC was found to be mediated in part by secretion of cathelicidin and was significantly increased by antibiotics. Studies in pet dogs with spontaneous chronic multi drug-resistant wound infections demonstrated clearance of bacteria and wound healing following repeated i.v. administration of activated allogeneic canine MSC. Thus, systemic therapy with activated MSC may be an effective new, non-antimicrobial approach to treatment of chronic, drug-resistant infections.

PMID: 28851894 [PubMed - indexed for MEDLINE]

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Amino Acid-Modified Conjugated Oligomer Self-Assembly Hydrogel for Efficient Capture and Specific Killing of Antibiotic-Resistant Bacteria.

ACS Appl Mater Interfaces. 2019 Apr 15;:

Authors: Zhao Q, Zhao Y, Lu Z, Tang Y

Abstract
Bacterial infection is one of main causes that threaten global human health. Especially, antibiotic-resistant bacteria like methicillin-resistant S. aureus (MRSA) lead to high mortality rate and more expensive treatment cost. Here, a novel amino-acid-modified conjugated oligomer OTE-D-Phe was synthesized by modifying the side-chain of conjugated oligo(thiophene ethynylene) with D-phenylalanine. By mixing Fmoc-L-Phe (9-fluorenylmethyloxycarbonyl-L-phenylalanin) with OTE-D-Phe, a new and biocompatible low molecular weight hydrogel (HG-2) was prepared through self-assembly. In solution, HG-2 can effectively capture bacteria spontaneously, such as E. coli and MRSA. Most importantly, the hydrogel has specific and strong antibacterial activity against methicillin-resistant S. aureus over methicillin-susceptible Staphylococcus aureus, Staphylococcus epidermidis and E. coli . Interestingly, when the hydrogel was put on a model surface, a piece of cloth, it also is able to selectively kill MRSA with low cell cytotoxicity. The antibacterial mechanism was investigated and demonstrated the HG-2 should interact with and physically break the cell wall and membrane, which lead to MRSA death. Therefore, this new conjugated oligomer-based hydrogel provides promising applications in disinfection and therapy of MRSA in hospital and in community.

PMID: 30985103 [PubMed - as supplied by publisher]

Gaining entry: A convergent synthetic strategy towards glycosylated cell‐penetrating peptides (GCPPs) and the systematic evaluation of their uptake efficiency and intracellular distribution in different cell lines is reported. The results highlight the importance and potential of peptide glycosylation for adjusting the penetrating efficiency and cytotoxicity of GCPPs.

Abstract

The cell membrane regulates the exchange of molecules and information with the external environment. However, this control barrier hinders the delivery of exogenous bioactive molecules that can be applied to correct cellular malfunctions. Therefore, the traffic of macromolecules across the cell membrane represents a great challenge for the development of the next generation of therapies and diagnostic methods. Cell‐penetrating peptides are short peptide sequences capable of delivering a broad range of biomacromolecules across the cellular membrane. However, penetrating peptides still suffer from limitations, mainly related to their lack of specificity and potential toxicity. Glycosylation has emerged as a potential promising strategy for the biological improvement of synthetic materials. In this work we have developed a new convergent strategy for the synthesis of penetrating peptides functionalized with glycan residues by an oxime bond connection. The uptake efficiency and intracellular distribution of these glycopeptides have been systematically characterized by means of flow cytometry and confocal microscopy and in zebrafish animal models. The incorporation of these glycan residues into the peptide structure influenced the internalization efficiency and cellular toxicity of the resulting glycopeptide hybrids in the different cell lines tested. The results reported herein highlight the potential of the glycosylation of penetrating peptides to modulate their activity.

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The Driving Force for the Acylation of β-Lactam Antibiotics by L,D-Transpeptidase 2: Quantum Mechanics/Molecular Mechanics (QM/MM) Study.

Chemphyschem. 2019 Apr 10;:

Authors: Ibeji CU, Lawal MM, Tolufashe GF, Govender T, Naicker T, Maguire GEM, Lamichhane G, Kruger HG, Honarparvar B

Abstract
β-lactam antibiotics, which are used to treat infectious diseases, are currently the most widely used class of antibiotics. This study focused on the chemical reactivity of five- and six-membered ring systems attached to the β-lactam ring. The ring strain energy (RSE), force constant (FC) of amide (C-N), acylation transition states and second-order perturbation stabilization energies of 13 basic structural units of β-lactam derivatives were computed using the M06-2X and G3/B3LYP multistep method. In the ring strain calculations, an isodesmic reaction scheme was used to obtain the total energies. RSE is relatively greater in the five-(1a-2c) compared to the six-membered ring systems except for 4b, which gives a RSE that is comparable to five-membered ring lactams. These variations were also observed in the calculated inter-atomic amide bond distances (C-N), which is why the six-membered ring lactams C-N bond are more rigid than those with five-membered ring lactams. The calculated ΔG# values from the acylation reaction of the lactams (involving the S-H group of the cysteine active residue from L,D transpeptidase 2) revealed a faster rate of C-N cleavage in the five-membered ring lactams especially in the 1-2 derivatives (17.58 kcal mol-1 ). This observation is also reflected in the calculated amide bond force constant (1.26 mDyn/A) indicating a weaker bond strength, suggesting that electronic factors (electron delocalization) play more of a role on reactivity of the β-lactam ring, than ring strain.

PMID: 30969480 [PubMed - as supplied by publisher]

Chimeric antigen receptor (CAR) T cell therapy has been successful in clinical trials against hematological cancers, but has experienced challenges in the treatment of solid tumors. One of the main difficulties lies in a paucity of tumor-specific targets that can serve as CAR recognition domains. We therefore focused on developing...

Aggregation‐induced emission (AIE) is a photoluminescence phenomenon in which a so‐called AIE luminogen (AIEgen) exhibits intense emission in the aggregated or solid state but only weak or no emission in the solution state. This Minireview investigates the crucial role that changes to the molecular structure of an AIEgen in the excited state (for example a π twist) have on the mechanism of AIE.

Abstract

Aggregation‐induced emission (AIE) is a photoluminescence phenomenon in which an AIE luminogen (AIEgen) exhibits intense emission in the aggregated or solid state but only weak or no emission in the solution state. Understanding the mechanism of AIE requires consideration of excited state molecular geometry (for example, a π twist). This Minireview examines the history of AIEgens with a focus on the representative AIEgen, tetraphenylethylene (TPE). The mechanisms of solution‐state quenching are reviewed and the crucial role of excited‐state molecular transformations for AIE is discussed. Finally, recent progress in understanding the relationship between excited state molecular transformations and AIE is overviewed for a range of different AIEgens.

Three strikes and you're out: A general nonpeptidic C₅N₂‐nanoparticle‐based platform for the delivery of molecules and nanomaterials to the cell nucleus was developed by adjusting intracellular trafficking (see picture). Because of the photoresponsive nature of the C₅N₂ NPs and their ability to enter the nucleus, enhanced chemotherapy, photothermal therapy, and photodynamic therapy were possible simultaneously.

Abstract

Intracellular targeting has the same potential as tissue targeting to increase therapy efficacy, especially for drugs that are toxic to DNA. By adjusting intracellular traffic, we developed a novel direct‐nucleus‐delivery platform based on C₅N₂ nanoparticles (NPs). Supramolecular interactions of C₅N₂ NPs with the cell membrane enhanced cell uptake; abundant edge amino groups promoted fast and effective rupture of early endosomes; and the appropriate size of the NPs was also crucial for size‐dependent nuclear entry. As a proof of concept, the platform was not only suitable for the effective delivery of molecular drugs/dyes (doxorubicin, hydroxycamptothecine, and propidium iodide) and MnO₂ nanoparticles to the nucleus, but was also photoresponsive for nucleus‐targeting photothermal therapy (PTT) and photodynamic therapy (PDT) to further greatly increase anticancer efficacy. This strategy might open the door to a new generation of nuclear‐targeted enhanced anticancer therapy.

Getting pro(drug)active: Bioorthogonal chemistry has transformed the field of prodrug activation. In particular, the inverse electron demand Diels Alder reaction has gained attention due to its high reaction rates and biocompatibility. This article discusses the concept of using tetrazines as an activator for prodrugs, and provides an overview of tetrazine‐based prodrug systems.

Abstract

Traditionally, prodrug activation has been limited to enzymatic triggers or gross physiological aberrations, such as pH, that offer low selectivity and control over dosage. In recent years, the field of prodrug activation chemistry has been transformed by the use of bioorthogonal reactions that can be carried out under biological conditions at sub‐millimolar concentrations, with the tetrazine‐mediated inverse electron demand Diels–Alder reaction amongst the most recognised. Their high reaction rates, chemoselectivity and excellent biocompatibility make tetrazines ideal small molecules for activating prodrugs. Recently the tetrazine moiety has been used as a prodrug for a pyridazine thus broadening the scope of prodrug systems. This article discusses the concept of using tetrazines as small‐molecule activators for prodrugs, and provides an overview of tetrazine‐based prodrug systems, with a particular focus on the recently reported prodrug–prodrug activation strategy.

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Production and characterization of a monoclonal antibody for Pefloxacin and mechanism study of antibody recognition.

Biosci Biotechnol Biochem. 2019 Apr;83(4):633-640

Authors: Zhang X, He K, Zhang D, Huang Z

Abstract
In this report, an artificial antigen (PFLX-BSA: Pefloxacin connected bovine serum albumin) was successfully prepared. The monoclonal antibody against pefloxacin was produced and characterized using a direct competitive ELISA. The linear range of detection was 0.115-6.564 µg/L. The limit of detection defined as IC15 was 0.170 ± 0.05 µg/L and the IC50 was 0.902 ± 0.03 µg/L. The antibody variable region genes were amplified, assembled, and sequenced. A three-dimensional structural model of the variable region was constructed to study the mechanism of antibody recognition using molecular docking analysis. Three predicted essential amino acids, Thr53, Arg97 of heavy chain and Thr52 of light chain, were mutated to verify the theoretical model. Three mutants lost binding activity significantly against pefloxacin as predicted. These may provide useful insights for studying antigen-antibody interaction mechanisms to improve antibody affinity maturation in vitro.

PMID: 30618329 [PubMed - indexed for MEDLINE]