scholarly journals Advancing the Therapeutic Potential of Indoleamides for Tuberculosis

2019 ◽  
Vol 63 (7) ◽  
Author(s):  
Shichun Lun ◽  
Rokeya Tasneen ◽  
Tridib Chaira ◽  
Jozef Stec ◽  
Oluseye K. Onajole ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Oral Formulation ◽  
Mycolic Acid ◽  
Infection Model ◽  
High Dose ◽  
Drug Resistant ◽  
Content Type ◽  
Mouse Infection ◽  
Novel Scaffold

ABSTRACT Indole-2-carboxamide derivatives are inhibitors of MmpL3, the cell wall-associated mycolic acid transporter of Mycobacterium tuberculosis. In the present study, we characterized indoleamide effects on bacterial cell morphology and reevaluated pharmacokinetics and in vivo efficacy using an optimized oral formulation. Morphologically, indoleamide-treated M. tuberculosis cells demonstrated significantly higher numbers of dimples near the poles or septum, which may serve as the mechanism of cell death for this bactericidal scaffold. Using the optimized formulation, an expanded-spectrum indoleamide, compound 2, showed significantly improved pharmacokinetic (PK) parameters and in vivo efficacy in mouse infection models. In a comparative study, compound 2 showed superior efficacy over compound 3 (NITD-304) in a high-dose aerosol mouse infection model. Since indoleamides are equally active on drug-resistant M. tuberculosis, these findings demonstrate the therapeutic potential of this novel scaffold for the treatment of both drug-susceptible and drug-resistant tuberculosis.

scholarly journals In VivoEfficacy of Human Simulated Regimens of Carbapenems and Comparator Agents against NDM-1-Producing Enterobacteriaceae

2013 ◽  
Vol 58 (3) ◽  
pp. 1671-1677 ◽  
Author(s):  
Dora E. Wiskirchen ◽  
Patrice Nordmann ◽  
Jared L. Crandon ◽  
David P. Nicolau
Keyword(s):  
Type Strain ◽  
Wild Type Strain ◽  
Similar Efficacy ◽  
Infection Model ◽  
High Dose ◽  
Wild Type ◽  
Prolonged Infusion ◽  
Content Type

ABSTRACTDoripenem and ertapenem have demonstrated efficacy against several NDM-1-producing isolatesin vivo, despite having high MICs. In this study, we sought to further characterize the efficacy profiles of humanized regimens of standard (500 mg given every 8 h) and high-dose, prolonged infusion of doripenem (2 g given every 8 h, 4-h infusion) and 1 g of ertapenem given intravenously every 24 h and the comparator regimens of ceftazidime at 2 g given every 8 h (2-h infusion), levofloxacin at 500 mg every 24 h, and aztreonam at 2 g every 6 h (1-h infusion) against a wider range of isolates in a murine thigh infection model. An isogenic wild-type strain and NDM-1-producingKlebsiella pneumoniaeand eight clinical NDM-1-producing members of the familyEnterobacteriaceaewere tested in immunocompetent- and neutropenic-mouse models. The wild-type strain was susceptible to all of the agents, while the isogenic NDM-1-producing strain was resistant to ceftazidime, doripenem, and ertapenem. Clinical NDM-1-producing strains were resistant to nearly all five of the agents (two were susceptible to levofloxacin). In immunocompetent mice, all of the agents produced ≥1-log10CFU reductions of the isogenic wild-type and NDM-1-producing strains after 24 h. Minimal efficacy of ceftazidime, aztreonam, and levofloxacin against the clinical NDM-1-producing strains was observed. However, despitein vitroresistance, ≥1-log10CFU reductions of six of eight clinical strains were achieved with high-dose, prolonged infusion of doripenem and ertapenem. Slight enhancements of doripenem activity over the standard doses were obtained with high-dose, prolonged infusion for three of the four isolates tested. Similar efficacy observations were noted in neutropenic mice. These data suggest that carbapenems are a viable treatment option for infections caused by NDM-1-producingEnterobacteriaceae.

scholarly journals Tridecaptin M, a New Variant Discovered in Mud Bacterium, Shows Activity against Colistin- and Extremely Drug-ResistantEnterobacteriaceae

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Manoj Jangra ◽  
Manpreet Kaur ◽  
Rushikesh Tambat ◽  
Rohit Rana ◽  
Sushil K. Maurya ◽  
...  
Keyword(s):  
Hemolytic Activity ◽  
World Health ◽  
Fourth Generation ◽  
Infection Model ◽  
Drug Resistant ◽  
Content Type ◽  
Extensively Drug Resistant ◽  
New Variant

ABSTRACTThe World Health Organization has categorized the Gram-negative superbugs, which are inherently impervious to many antibiotics, as critical priority pathogens due to the lack of effective treatments. The breach in our last-resort antibiotic (i.e., colistin) by extensively drug-resistant and pan-drug-resistantEnterobacteriaceaestrains demands the immediate development of new therapies. In the present study, we report the discovery of tridecaptin M, a new addition to the family, and its potential against colistin-resistantEnterobacteriaceae in vitroandin vivo. Also, we performed mode-of-action studies using various fluorescent probes and studied the hemolytic activity and mammalian cytotoxicity in two cell lines. Tridecaptin M displayed strong antibacterial activity (MICs of 2 to 8 μg ml−1) against clinical strains ofKlebsiella pneumoniae(which were resistant to colistin, carbapenems, third- and fourth-generation cephalosporins, fluoroquinolones, fosfomycin, and other antibiotics) andmcr-1-positiveEscherichia colistrains. Unlike polymyxins, tridecaptin M did not permeabilize the outer membrane or cytoplasmic membrane. It blocked ATP synthesis in bacteria by dissipating the proton motive force. The compound exhibited negligible acquired resistance, lowin vitrocytotoxicity and hemolytic activity, and no significant acute toxicity in mice. It also showed promising efficacy in a thigh infection model of colistin-resistantK. pneumoniae. Altogether, these results demonstrate the future prospects of this class of antibiotics to address the unmet medical need to circumvent colistin resistance in extensively drug-resistantEnterobacteriaceaeinfections. The work also emphasizes the importance of natural products in our shrunken drug discovery pipeline.

scholarly journals Efficacy of Humanized High-Dose Meropenem, Cefepime, and Levofloxacin against Enterobacteriaceae Isolates Producing Verona Integron-Encoded Metallo-β-Lactamase (VIM) in a Murine Thigh Infection Model

2015 ◽  
Vol 59 (11) ◽  
pp. 7145-7147 ◽  
Author(s):  
Islam M. Ghazi ◽  
Jared L. Crandon ◽  
Emil P. Lesho ◽  
Patrick McGann ◽  
David P. Nicolau
Keyword(s):  
Murine Model ◽  
Infection Model ◽  
High Dose ◽  
Content Type ◽  
High Mics

ABSTRACTWe aimed to describe thein vivoactivity of humanized pharmacokinetic exposures of meropenem and comparators against Verona integron-encoded metallo-β-lactamase (MBL) (VIM)-producingEnterobacteriaceaein a murine model. Levofloxacin activity was predicted by its MIC, and cefepime activity displayed variability, whereas meropenem produced a >1 log CFU reduction against all isolates despite high MICs indicative of resistance. Our results suggest that despitein vitroresistance, high-dose meropenem may be a possible option against infections caused byEnterobacteriaceaeproducing MBL-type carbapenemases.

scholarly journals Antimicrobial Effects of Ibuprofen Combined with Standard of Care Antimicrobials against Cystic Fibrosis Pathogens

2021 ◽  
Author(s):  
Qingquan Chen ◽  
Marleini Ilanga ◽  
Sabona B Simbassa ◽  
Bhagath Chirra ◽  
Kush N Shah ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Antimicrobial Activity ◽  
Standard Of Care ◽  
Infection Model ◽  
High Dose ◽  
Synergistic Activity ◽  
Drug Resistant ◽  
Anti Inflammatory

Cystic Fibrosis (CF) is a common fatal genetic disease caused by mutations happened to cystic fibrosis transmembrane conductance regulator (CFTR) gene. Lungs of CF patients are often colonized or infected with microorganisms. Drug resistant bacterial infection has been problematic in cystic fibrosis patient. The chronic bacterial infections and concomitant airway inflammation could damage the lung and lead to respiratory failure. Several clinical trials have demonstrated that high-dose ibuprofen reduces the rate of pulmonary function decline in CF patients. This beneficial effect has been attributed to the anti-inflammatory properties of ibuprofen. Previously, we have confirmed that high-dose ibuprofen demonstrated antimicrobial activity against P. aeruginosa in in vitro and in vivo. However, no study has examined the antimicrobial effect of combining ibuprofen with standard-of-care (SoC) antimicrobials. Here, we evaluated possible synergistic activity of combinations of common nonsteroidal anti-inflammatory drugs (NSAIDs), namely, aspirin, naproxen, and ibuprofen, with commonly used antibiotics for CF patients. The drug combinations were screened against different CF clinical isolates. Drugs that demonstrated efficacy in the presence of ibuprofen were further verified synergistic effects between these antimicrobials and NSAIDs. Finally, the survival analysis of an P. aeruginosa murine infection model was used to demonstrate the efficacy of synergistic combination. Our results suggest that combinations of ibuprofen with commonly used antibiotics demonstrate synergistic antimicrobial activity against drug resistant, clinical bacterial strains in in vitro. The efficacy of combination ceftazidime and ibuprofen was demonstrated in in vivo.

scholarly journals Efficacy of OH-CATH30 and Its Analogs against Drug-Resistant BacteriaIn Vitroand in Mouse Models

2012 ◽  
Vol 56 (6) ◽  
pp. 3309-3317 ◽  
Author(s):  
Sheng-An Li ◽  
Wen-Hui Lee ◽  
Yun Zhang
Keyword(s):  
Mouse Models ◽  
Bacterial Infections ◽  
Resistant Bacteria ◽  
Infection Model ◽  
Drug Resistant ◽  
Content Type ◽  
E Coli ◽  
Drug Resistant Bacteria

ABSTRACTAntimicrobial peptides (AMPs) have been considered alternatives to conventional antibiotics for drug-resistant bacterial infections. However, their comparatively high toxicity toward eukaryotic cells and poor efficacyin vivohamper their clinical application. OH-CATH30, a novel cathelicidin peptide deduced from the king cobra, possesses potent antibacterial activityin vitro. The objective of this study is to evaluate the efficacy of OH-CATH30 and its analog OH-CM6 against drug-resistant bacteriain vitroandin vivo. The MICs of OH-CATH30 and OH-CM6 ranged from 1.56 to 12.5 μg/ml against drug-resistant clinical isolates of several pathogenic species, includingEscherichia coli,Pseudomonas aeruginosa, and methicillin-resistantStaphylococcus aureus. The MICs of OH-CATH30 and OH-CM6 were slightly altered in the presence of 25% human serum. OH-CATH30 and OH-CM6 killedE. coliquickly (within 60 min) by disrupting the bacterial cytoplasmic membrane. Importantly, the 50% lethal doses (LD50) of OH-CATH30 and OH-CM6 in mice following intraperitoneal (i.p.) injection were 120 mg/kg of body weight and 100 mg/kg, respectively, and no death was observed at any dose up to 160 mg/kg following subcutaneous (s.c.) injection. Moreover, 10 mg/kg OH-CATH30 or OH-CM6 significantly decreased the bacterial counts as well as the inflammatory response in a mouse thigh infection model and rescued infected mice in a bacteremia model induced by drug-resistantE. coli. Taken together, our findings demonstrate that the natural cathelicidin peptide OH-CATH30 and its analogs exhibit relatively low toxicity and potent efficacy in mouse models, indicating that they may have therapeutic potential against the systemic infections caused by drug-resistant bacteria.

scholarly journals In vitro selection predicts malaria parasite resistance to dihydroorotate dehydrogenase inhibitors in a mouse infection model

2019 ◽  
Vol 11 (521) ◽  
pp. eaav1636 ◽  
Author(s):  
Rebecca E. K. Mandt ◽  
Maria Jose Lafuente-Monasterio ◽  
Tomoyo Sakata-Kato ◽  
Madeline R. Luth ◽  
Delfina Segura ◽  
...  
Keyword(s):  
Mouse Model ◽  
In Vitro Selection ◽  
Infection Model ◽  
Drug Resistant ◽  
Dihydroorotate Dehydrogenase ◽  
Mouse Infection Model ◽  
Development Of Resistance ◽  
Mouse Infection

Resistance has developed in Plasmodium malaria parasites to every antimalarial drug in clinical use, prompting the need to characterize the pathways mediating resistance. Here, we report a framework for assessing development of resistance of Plasmodium falciparum to new antimalarial therapeutics. We investigated development of resistance by P. falciparum to the dihydroorotate dehydrogenase (DHODH) inhibitors DSM265 and DSM267 in tissue culture and in a mouse model of P. falciparum infection. We found that resistance to these drugs arose rapidly both in vitro and in vivo. We identified 13 point mutations mediating resistance in the parasite DHODH in vitro that overlapped with the DHODH mutations that arose in the mouse infection model. Mutations in DHODH conferred increased resistance (ranging from 2- to ~400-fold) to DHODH inhibitors in P. falciparum in vitro and in vivo. We further demonstrated that the drug-resistant parasites carrying the C276Y mutation had mitochondrial energetics comparable to the wild-type parasite and also retained their fitness in competitive growth experiments. Our data suggest that in vitro selection of drug-resistant P. falciparum can predict development of resistance in a mouse model of malaria infection.

scholarly journals Efficacy of Humanized Carbapenem Exposures against New Delhi Metallo-β-Lactamase (NDM-1)-Producing Enterobacteriaceae in a Murine Infection Model

2013 ◽  
Vol 57 (8) ◽  
pp. 3936-3940 ◽  
Author(s):  
Dora E. Wiskirchen ◽  
Patrice Nordmann ◽  
Jared L. Crandon ◽  
David P. Nicolau
Keyword(s):  
Maximal Activity ◽  
Bacterial Density ◽  
Infection Model ◽  
High Dose ◽  
New Delhi ◽  
Wild Type ◽  
Content Type ◽  
Immunocompetent Mice

ABSTRACTEnterobacteriaceaeproducing the novel carbapenemase New Delhi metallo-β-lactamase (NDM-1) are emerging worldwide. While these organisms often display high levels ofin vitroresistance to multiple antibiotics,in vivoefficacy data are lacking. Here, the activities of humanized ertapenem and doripenem exposures were characterized against a wild-typeK. pneumoniaeand its derived isogenic strains harboring either an NDM-1 or KPC-2 plasmid in immunocompetent mice. In addition, four clinical isolates expressing NDM-1 were evaluated. Human-simulated regimens of ertapenem at 1 g every 24 h and high-dose, prolonged infusion of doripenem at 2 g every 8 h as a 4-h infusion were evaluated over 24 h, and efficacy was determined by the change in bacterial density compared to that in 24-h growth controls. CFU reductions in bacterial density of greater than 1 log unit were observed against the wild-type strain as well as the derived isogenic NDM-1 strain, while no reduction was observed against the derived KPC-2 strain. Postexposure MICs confirmed thein vitromaintenance of the ertapenem resistance marker in both the NDM-1 and KPC-2 strains. Similar to the case for the isogenically derived NDM-1 strain, bacterial density was reduced at 24 h against all four clinical NDM-1 isolates showing variable levels of MICs for carbapenems, with near-maximal activity of both agents occurring when the doripenem MIC was ≤8 μg/ml. While carbapenem monotherapy does not appear to be an option against KPC-based infections, these data suggest that carbapenem monotherapy may be a viable option for treating NDM-1-producingEnterobacteriaceaeunder certain conditions, and this warrants furtherin vivoexploration.

scholarly journals Mechanistic insights into synergy between nalidixic acid and tetracycline against clinical isolates of Acinetobacter baumannii and Escherichia coli

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Amit Gaurav ◽  
Varsha Gupta ◽  
Sandeep K. Shrivastava ◽  
Ranjana Pathania
Keyword(s):  
Escherichia Coli ◽  
Acinetobacter Baumannii ◽  
Nalidixic Acid ◽  
Bacterial Infections ◽  
Clinical Isolates ◽  
Hospital Environment ◽  
Infection Model ◽  
Drug Resistant ◽  
E Coli

AbstractThe increasing prevalence of antimicrobial resistance has become a global health problem. Acinetobacter baumannii is an important nosocomial pathogen due to its capacity to persist in the hospital environment. It has a high mortality rate and few treatment options. Antibiotic combinations can help to fight multi-drug resistant (MDR) bacterial infections, but they are rarely used in the clinics and mostly unexplored. The interaction between bacteriostatic and bactericidal antibiotics are mostly reported as antagonism based on the results obtained in the susceptible model laboratory strain Escherichia coli. However, in the present study, we report a synergistic interaction between nalidixic acid and tetracycline against clinical multi-drug resistant A. baumannii and E. coli. Here we provide mechanistic insight into this dichotomy. The synergistic combination was studied by checkerboard assay and time-kill curve analysis. We also elucidate the mechanism behind this synergy using several techniques such as fluorescence spectroscopy, flow cytometry, fluorescence microscopy, morphometric analysis, and real-time polymerase chain reaction. Nalidixic acid and tetracycline combination displayed synergy against most of the MDR clinical isolates of A. baumannii and E. coli but not against susceptible isolates. Finally, we demonstrate that this combination is also effective in vivo in an A. baumannii/Caenorhabditis elegans infection model (p < 0.001)

scholarly journals ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Ørjan Samuelsen ◽  
Ove Alexander Høgmoen Åstrand ◽  
Christopher Fröhlich ◽  
Adam Heikal ◽  
Susann Skagseth ◽  
...  
Keyword(s):  
Active Site ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Carbapenem Resistance ◽  
Functional Space ◽  
Bactericidal Effect ◽  
Gram Negative ◽  
Content Type

ABSTRACT Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo-β-lactamase (MBL) families. The recent introduction of SBL carbapenemase inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Here, we present ZN148, a zinc-chelating MBL-inhibitor capable of restoring the bactericidal effect of meropenem and in vitro clinical susceptibility to carbapenems in >98% of a large international collection of MBL-producing clinical Enterobacterales strains (n = 234). Moreover, ZN148 was able to potentiate the effect of meropenem against NDM-1-producing Klebsiella pneumoniae in a murine neutropenic peritonitis model. ZN148 showed no inhibition of the human zinc-containing enzyme glyoxylase II at 500 μM, and no acute toxicity was observed in an in vivo mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by ∼30%, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modeling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor that is capable of operating in a functional space not presently filled by any clinically approved compound.

scholarly journals In VivoEfficacy of Anuran Trypsin Inhibitory Peptides against Staphylococcal Skin Infection and the Impact of Peptide Cyclization

2015 ◽  
Vol 59 (4) ◽  
pp. 2113-2121 ◽  
Author(s):  
U. Malik ◽  
O. N. Silva ◽  
I. C. M. Fensterseifer ◽  
L. Y. Chan ◽  
R. J. Clark ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Cyclic Peptide ◽  
Sequence Similarity ◽  
Infection Model ◽  
Content Type ◽  
Wide Range ◽  
Inhibitory Activities ◽  
The Impact

ABSTRACTStaphylococcus aureusis a virulent pathogen that is responsible for a wide range of superficial and invasive infections. Its resistance to existing antimicrobial drugs is a global problem, and the development of novel antimicrobial agents is crucial. Antimicrobial peptides from natural resources offer potential as new treatments against staphylococcal infections. In the current study, we have examined the antimicrobial properties of peptides isolated from anuran skin secretions and cyclized synthetic analogues of these peptides. The structures of the peptides were elucidated by nuclear magnetic resonance (NMR) spectroscopy, revealing high structural and sequence similarity with each other and with sunflower trypsin inhibitor 1 (SFTI-1). SFTI-1 is an ultrastable cyclic peptide isolated from sunflower seeds that has subnanomolar trypsin inhibitory activity, and this scaffold offers pharmaceutically relevant characteristics. The five anuran peptides were nonhemolytic and noncytotoxic and had trypsin inhibitory activities similar to that of SFTI-1. They demonstrated weakin vitroinhibitory activities againstS. aureus, but several had strong antibacterial activities againstS. aureusin anin vivomurine wound infection model. pYR, an immunomodulatory peptide fromRana sevosa, was the most potent, with complete bacterial clearance at 3 mg · kg−1. Cyclization of the peptides improved their stability but was associated with a concomitant decrease in antimicrobial activity. In summary, these anuran peptides are promising as novel therapeutic agents for treating infections from a clinically resistant pathogen.

Sign in / Sign up

Export Citation Format

Share Document