The Experts below are selected from a list of 26088 Experts worldwide ranked by ideXlab platform
Stuart W. Mccombie - One of the best experts on this subject based on the ideXlab platform.
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Gamma-Lactams and related compounds as cholesterol absorption inhibitors: homologs of the beta-lactam cholesterol absorption inhibitor SCH 484611
Bioorganic & Medicinal Chemistry Letters, 1995Co-Authors: Sundeep Dugar, Razia Rizvi, M.e. Snow, John W. Clader, Michael P. Kirkup, Harry R Davis, Stuart W. MccombieAbstract:Abstract Our search for potent cholesterol absorption inhibitors led to the discovery of the β-lactam SCH 48461. Structure activity relationship studies prompted us to this study of γ-Lactams, ring homologs of β-lactam SCH 48461, to determine their potential as cholesterol absorption inhibitors. The results indicate that the γ-Lactams have moderate cholesterol absorption inhibitory properties.
Yeongil Kim - One of the best experts on this subject based on the ideXlab platform.
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crystal structures of penicillin binding protein d2 from listeria monocytogenes and structural basis for antibiotic specificity
Antimicrobial Agents and Chemotherapy, 2018Co-Authors: Jaehee Jeong, Hyung Jin Cha, Yeongil KimAbstract:β-Lactam antibiotics that inhibit penicillin-binding proteins (PBPs) have been widely used in the treatment of bacterial infections. However, the molecular basis underlying the different inhibitory potencies of β-Lactams against specific PBPs is not fully understood. Here, we present the crystal structures of penicillin-binding protein D2 (PBPD2) from Listeria monocytogenes, a Gram-positive foodborne bacterial pathogen that causes listeriosis in humans. The acylated structures in complex with four antibiotics (penicillin G, ampicillin, cefotaxime, and cefuroxime) revealed that the β-lactam core structures were recognized by a common set of residues; however, the R1 side chains of each antibiotic participate in different interactions with PBPD2. In addition, the structural complementarities between the side chains of β-Lactams and the enzyme were found to be highly correlated with the relative reactivities of penam or cephem antibiotics against PBPD2. Our study provides the structural basis for the inhibition of PBPD2 by clinically important β-lactam antibiotics that are commonly used in listeriosis treatment. Our findings imply that the modification of β-lactam side chains based on structural complementarity could be useful for the development of potent inhibitors against β-lactam-resistant PBPs.
Deborah T Hung - One of the best experts on this subject based on the ideXlab platform.
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loss of a class a penicillin binding protein alters β lactam susceptibilities in mycobacterium tuberculosis
ACS Infectious Diseases, 2016Co-Authors: Carl N Wivagg, Samantha Wellington, James Gomez, Deborah T HungAbstract:Recent studies have renewed interest in β-lactam antibiotics as a potential treatment for Mycobacterium tuberculosis infection. To explore the opportunities and limitations of this approach, we sought to better understand potential resistance mechanisms to β-lactam antibiotics in M. tuberculosis. We identified mutations in the penicillin-binding protein (PBP) ponA2 that were able to confer some degree of resistance to the cephalosporin subclass of β-Lactams. Surprisingly, deletion of ponA2 also confers resistance, demonstrating that β-lactam resistance can spontaneously arise from PBP loss of function. We show that ponA2 mutants resistant to the cephalosporin subclass of β-Lactams in fact show increased susceptibility to meropenem, a carbapenem that is known to target l,d-transpeptidases, thereby suggesting that in the absence of PonA2, an alternative mode of peptidoglycan synthesis likely becomes essential. Consistent with this hypothesis, a negative genetic selection identified the l,d-transpeptidase ld...
Natalie C J Strynadka - One of the best experts on this subject based on the ideXlab platform.
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structural basis for the beta lactam resistance of pbp2a from methicillin resistant staphylococcus aureus
Nature Structural & Molecular Biology, 2002Co-Authors: Daniel Lim, Natalie C J StrynadkaAbstract:The multiple antibiotic resistance of methicillin-resistant strains of Staphylococcus aureus (MRSA) has become a major clinical problem worldwide. The key determinant of the broad-spectrum beta-lactam resistance in MRSA strains is the penicillin-binding protein 2a (PBP2a). Because of its low affinity for beta-Lactams, PBP2a provides transpeptidase activity to allow cell wall synthesis at beta-lactam concentrations that inhibit the beta-lactam-sensitive PBPs normally produced by S. aureus. The crystal structure of a soluble derivative of PBP2a has been determined to 1.8 A resolution and provides the highest resolution structure for a high molecular mass PBP. Additionally, structures of the acyl-PBP complexes of PBP2a with nitrocefin, penicillin G and methicillin allow, for the first time, a comparison of an apo and acylated resistant PBP. An analysis of the PBP2a active site in these forms reveals the structural basis of its resistance and identifies features in newly developed beta-Lactams that are likely important for high affinity binding.
Gyanu Lamichhane - One of the best experts on this subject based on the ideXlab platform.
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select β lactam combinations exhibit synergy against mycobacterium abscessus in vitro
Antimicrobial Agents and Chemotherapy, 2019Co-Authors: Elizabeth Storyroller, Emily C Maggioncalda, Gyanu LamichhaneAbstract:Mycobacterium abscessus is a nontuberculous mycobacterium that causes invasive pulmonary infections in patients with structural lung disease. M. abscessus is intrinsically resistant to several classes of antibiotics, and an increasing number of strains isolated from patients exhibit resistance to most antibiotics considered for treatment of infections by this mycobacterium. Therefore, there is an unmet need for new regimens with improved efficacy to treat this disease. Synthesis of the essential cell wall peptidoglycan in M. abscessus is achieved via two enzyme classes, l,d- and d,d-transpeptidases, with each class preferentially inhibited by different subclasses of β-lactam antibiotics. We hypothesized that a combination of two β-Lactams that comprehensively inhibit the two enzyme classes will exhibit synergy in killing M. abscessus Paired combinations of antibiotics tested for in vitro synergy against M. abscessus included dual β-Lactams, a β-lactam and a β-lactamase inhibitor, and a β-lactam and a rifamycin. Of the initial 206 combinations screened, 24 pairs exhibited synergy. A total of 13/24 pairs were combinations of two β-Lactams, and 12/24 pairs brought the MICs of both drugs to within the therapeutic range. Additionally, synergistic drug pairs significantly reduced the frequency of selection of spontaneous resistant mutants. These novel combinations of currently available antibiotics may offer viable immediate treatment options against highly-resistant M. abscessus infections.
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in vitro activity of the new β lactamase inhibitors relebactam and vaborbactam in combination with β Lactams against mycobacterium abscessus complex clinical isolates
Antimicrobial Agents and Chemotherapy, 2019Co-Authors: Amit Kaushik, Gyanu Lamichhane, Nicole C Ammerman, Jin Lee, Olumide Martins, Barry N Kreiswirth, Nicole M Parrish, Eric L NuermbergerAbstract:Pulmonary disease due to infection with Mycobacterium abscessus complex (MABC) is notoriously difficult to treat, in large part due to the intrinsic resistance of MABC strains to most antibiotics, including β-Lactams. MABC organisms express a broad-spectrum β-lactamase that is resistant to traditional β-lactam-based β-lactamase inhibitors but inhibited by a newer non-β-lactam-based β-lactamase inhibitor, avibactam. Consequently, the susceptibility of MABC members to some β-Lactams is increased in the presence of avibactam. Therefore, we hypothesized that two new non-β-lactam-based β-lactamase inhibitors, relebactam and vaborbactam, would also increase the susceptibility of MABC organisms to β-Lactams. The objective of the present study was to evaluate the in vitro activity of various marketed β-Lactams alone and in combination with either relebactam or vaborbactam against multidrug-resistant MABC clinical isolates. Our data demonstrate that both β-lactamase inhibitors significantly improved the anti-MABC activity of many carbapenems (including imipenem and meropenem) and cephalosporins (including cefepime, ceftaroline, and cefuroxime). As a meropenem-vaborbactam combination is now marketed and an imipenem-relebactam combination is currently in phase III trials, these fixed combinations may become the β-Lactams of choice for the treatment of MABC infections. Furthermore, given the evolving interest in dual β-lactam regimens, our results identify select cephalosporins, such as cefuroxime, with superior activity in the presence of a β-lactamase inhibitor that are deserving of further evaluation in combination with these carbapenem-β-lactamase inhibitor products.
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select β lactam combinations exhibit synergy against mycobacterium abscessus in vitro
bioRxiv, 2019Co-Authors: Elizabeth Storyroller, Emily C Maggioncalda, Gyanu LamichhaneAbstract:Mycobacterium abscessus (Mab) is a nontuberculous mycobacterium that causes invasive pulmonary infections in patients with structural lung disease. Mab is intrinsically resistant to several classes of antibiotics and an increasing number of strains isolated from patients exhibit resistance to most antibiotics considered for treatment of Mab infections. Therefore, there is an unmet need for new regimens with improved efficacy to treat this disease. Synthesis of the essential cell wall peptidoglycan in Mab is achieved via two enzyme classes, L,D- and D-D-transpeptidases, with each class preferentially inhibited by different subclasses of {beta}-lactam antibiotics. We hypothesized that a combination of two {beta}-Lactams that comprehensively inhibit the two enzyme classes will exhibit synergy in killing Mab. Paired combinations of antibiotics tested for in vitro synergy against Mab included dual {beta}-Lactams, a {beta}-lactam and a {beta}-lactamase inhibitor, and a {beta}-lactam and a rifamycin. Of the initial 206 combinations screened, 24 pairs exhibited synergy. 13/24 pairs were combinations of two {beta}-Lactams. 12/24 pairs brought the minimum inhibitory concentrations of both drugs to within the therapeutic range. Additionally, synergistic drug pairs significantly reduced the frequency of selection of spontaneous resistant mutants. These novel combinations of currently available antibiotics may offer viable immediate treatment options against highly resistant Mab infections.
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in vitro activity of the new β lactamase inhibitors relebactam and vaborbactam in combination with β Lactams against mycobacterium abscessus complex clinical isolates
bioRxiv, 2018Co-Authors: Amit Kaushik, Gyanu Lamichhane, Nicole C Ammerman, Jin Lee, Olumide Martins, Barry N Kreiswirth, Nicole M Parrish, Eric L NuermbergerAbstract:Abstract Pulmonary disease due to infection with Mycobacterium abscessus complex (MABC) is notoriously difficult to treat, in large part due to MABC’s intrinsic resistance to most antibiotics, including β-Lactams. MABC organisms express a broad-spectrum β-lactamase that is resistant to traditional β-lactam-based β-lactamase inhibitors but inhibited by a newer non-β-lactam-based β-lactamase inhibitor, avibactam. Consequently, the susceptibility of MABC to some β-Lactams is increased in the presence of avibactam. Therefore, we hypothesized that two new non-β-lactam-based β-lactamase inhibitors, relebactam and vaborbactam, would also increase susceptibility of MABC to β-Lactams. The objective of the present study was to evaluate the in vitro activity of various marketed β-Lactams alone and in combination with either relebactam or vaborbactam against multidrug-resistant MABC clinical isolates. Our data demonstrate that both β-lactamase inhibitors significantly improved the anti-MABC activity of many carbapenems (including imipenem and meropenem) and cephalosporins (including cefepime, ceftaroline, and cefuroxime). As a meropenem/vaborbactam combination is now marketed and an imipenem/relebactam combination is currently in phase III trials, these fixed combinations may become the β-Lactams of choice for the treatment of MABC infections. Furthermore, given the evolving interest in dual β-lactam regimens, our results identify select cephalosporins, such as cefuroxime, with superior activity in the presence of a β-lactamase inhibitor, deserving of further evaluation in combination with these carbapenem/β-lactamase inhibitor products.
