scholarly journals Recent Advances in Mode of Action and Biosynthesis Studies of the Clinically Used Antibiotic Fidaxomicin

2020 ◽  
Vol 74 (4) ◽  
pp. 270-273 ◽  
Author(s):  
Andrea Dorst ◽  
Erik Jung ◽  
Karl Gademann
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Natural Product ◽  
Mode Of Action ◽  
Bacterial Infections ◽  
Biosynthetic Pathway ◽  
Antibacterial Activities ◽  
Next Generation ◽  
Unique Mode ◽  
Recent Advances

The natural product antibiotic fidaxomicin is a marketed drug for the treatment of bacterial infections in the gut. Due to its promising in vitro activities against Mycobacterium tuberculosis, the development of next generation fidaxomicin analogs is of great interest. This article reviews the most recent advances, including the elucidation of a unique mode of action by cryo-EM structures, and the efforts towards the clarification of the biosynthetic pathway. Moreover, known fidaxomicin analogs and their reported antibacterial activities are summarized.

scholarly journals In Vitro Evaluation of CBR-2092, a Novel Rifamycin-Quinolone Hybrid Antibiotic: Studies of the Mode of Action in Staphylococcus aureus

2008 ◽  
Vol 52 (7) ◽  
pp. 2313-2323 ◽  
Author(s):  
Gregory T. Robertson ◽  
Eric J. Bonventre ◽  
Timothy B. Doyle ◽  
Qun Du ◽  
Leonard Duncan ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Rna Polymerase ◽  
Mode Of Action ◽  
Bacterial Infections ◽  
Dna Gyrase ◽  
Topoisomerase Iv ◽  
Dna Topoisomerase ◽  
Resistant Variant ◽  
Proven Efficacy

ABSTRACT Rifamycins have proven efficacy in the treatment of persistent bacterial infections. However, the frequency with which bacteria develop resistance to rifamycin agents restricts their clinical use to antibiotic combination regimens. In a program directed toward the synthesis of rifamycins with a lower propensity to elicit resistance development, a series of compounds were prepared that covalently combine rifamycin and quinolone pharmacophores to form stable hybrid antibacterial agents. We describe mode-of-action studies with Staphylococcus aureus of CBR-2092, a novel hybrid that combines the rifamycin SV and 4H-4-oxo-quinolizine pharmacophores. In biochemical studies, CBR-2092 exhibited rifampin-like potency as an inhibitor of RNA polymerase, was an equipotent (balanced) inhibitor of DNA gyrase and DNA topoisomerase IV, and retained activity against a prevalent quinolone-resistant variant. Macromolecular biosynthesis studies confirmed that CBR-2092 has rifampin-like effects on RNA synthesis in rifampin-susceptible strains and quinolone-like effects on DNA synthesis in rifampin-resistant strains. Studies of mutant strains that exhibited reduced susceptibility to CBR-2092 further substantiated RNA polymerase as the primary cellular target of CBR-2092, with DNA gyrase and DNA topoisomerase IV being secondary and tertiary targets, respectively, in strains exhibiting preexisting rifampin resistance. In contrast to quinolone comparator agents, no strains with altered susceptibility to CBR-2092 were found to exhibit changes consistent with altered efflux properties. The combined data indicate that CBR-2092 may have potential utility in monotherapy for the treatment of persistent S. aureus infections.

scholarly journals Curative Treatment of Severe Gram-Negative Bacterial Infections by a New Class of Antibiotics Targeting LpxC

mBio ◽  
2017 ◽  
Vol 8 (4) ◽  
Author(s):  
Nadine Lemaître ◽  
Xiaofei Liang ◽  
Javaria Najeeb ◽  
Chul-Jin Lee ◽  
Marie Titecat ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Biosynthetic Pathway ◽  
Lipid A ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Drug Resistant ◽  
Bubonic Plague ◽  
Gram Negative ◽  
New Class

ABSTRACT The infectious diseases caused by multidrug-resistant bacteria pose serious threats to humankind. It has been suggested that an antibiotic targeting LpxC of the lipid A biosynthetic pathway in Gram-negative bacteria is a promising strategy for curing Gram-negative bacterial infections. However, experimental proof of this concept is lacking. Here, we describe our discovery and characterization of a biphenylacetylene-based inhibitor of LpxC, an essential enzyme in the biosynthesis of the lipid A component of the outer membrane of Gram-negative bacteria. The compound LPC-069 has no known adverse effects in mice and is effective in vitro against a broad panel of Gram-negative clinical isolates, including several multiresistant and extremely drug-resistant strains involved in nosocomial infections. Furthermore, LPC-069 is curative in a murine model of one of the most severe human diseases, bubonic plague, which is caused by the Gram-negative bacterium Yersinia pestis. Our results demonstrate the safety and efficacy of LpxC inhibitors as a new class of antibiotic against fatal infections caused by extremely virulent pathogens. The present findings also highlight the potential of LpxC inhibitors for clinical development as therapeutics for infections caused by multidrug-resistant bacteria. IMPORTANCE The rapid spread of antimicrobial resistance among Gram-negative bacilli highlights the urgent need for new antibiotics. Here, we describe a new class of antibiotics lacking cross-resistance with conventional antibiotics. The compounds inhibit LpxC, a key enzyme in the lipid A biosynthetic pathway in Gram-negative bacteria, and are active in vitro against a broad panel of clinical isolates of Gram-negative bacilli involved in nosocomial and community infections. The present study also constitutes the first demonstration of the curative treatment of bubonic plague by a novel, broad-spectrum antibiotic targeting LpxC. Hence, the data highlight the therapeutic potential of LpxC inhibitors against a wide variety of Gram-negative bacterial infections, including the most severe ones caused by Y. pestis and by multidrug-resistant and extensively drug-resistant carbapenemase-producing strains. IMPORTANCE The rapid spread of antimicrobial resistance among Gram-negative bacilli highlights the urgent need for new antibiotics. Here, we describe a new class of antibiotics lacking cross-resistance with conventional antibiotics. The compounds inhibit LpxC, a key enzyme in the lipid A biosynthetic pathway in Gram-negative bacteria, and are active in vitro against a broad panel of clinical isolates of Gram-negative bacilli involved in nosocomial and community infections. The present study also constitutes the first demonstration of the curative treatment of bubonic plague by a novel, broad-spectrum antibiotic targeting LpxC. Hence, the data highlight the therapeutic potential of LpxC inhibitors against a wide variety of Gram-negative bacterial infections, including the most severe ones caused by Y. pestis and by multidrug-resistant and extensively drug-resistant carbapenemase-producing strains.

scholarly journals In Vitro and In Vivo Antibacterial Activities of SM-216601, a New Broad-Spectrum Parenteral Carbapenem

2005 ◽  
Vol 49 (10) ◽  
pp. 4185-4196 ◽  
Author(s):  
Yutaka Ueda ◽  
Katsunori Kanazawa ◽  
Ken Eguchi ◽  
Koji Takemoto ◽  
Yoshiro Eriguchi ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Antibacterial Activities ◽  
Multiresistant Pathogens ◽  
E Coli ◽  
Wide Range ◽  
Agar Dilution ◽  
Resistant Strains ◽  
Mrsa Strains

ABSTRACT SM-216601 is a novel parenteral 1β-methylcarbapenem. In agar dilution susceptibility testing, the MIC of SM-216601 for 90% of the methicillin-resistant Staphylococcus aureus (MRSA) strains tested (MIC90) was 2 μg/ml, which was comparable to those of vancomycin and linezolid. SM-216601 was also very potent against Enterococcus faecium, including vancomycin-resistant strains (MIC90 = 8 μg/ml). SM-216601 exhibited potent activity against penicillin-resistant Streptococcus pneumoniae, ampicillin-resistant Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, with MIC90s of less than 0.5 μg/ml, and intermediate activity against Citrobacter freundii, Enterobacter cloacae, Serratia marcescens, and Pseudomonas aeruginosa. The therapeutic efficacy of SM-216601 against experimentally induced infections in mice caused by S. aureus, E. faecium, E. coli, and P. aeruginosa reflected its in vitro activity and plasma level. Thus, SM-216601 is a promising candidate for nosocomial bacterial infections caused by a wide range of gram-positive and gram-negative bacteria, including multiresistant pathogens.

scholarly journals Mn(III) Pyrophosphate as an Efficient Tool for Studying the Mode of Action of Isoniazid on the InhA Protein of Mycobacterium tuberculosis

2002 ◽  
Vol 46 (7) ◽  
pp. 2137-2144 ◽  
Author(s):  
Michel Nguyen ◽  
Annaïk Quémard ◽  
Sylvain Broussy ◽  
Jean Bernadou ◽  
Bernard Meunier
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Biosynthetic Pathway ◽  
Acyl Carrier Protein ◽  
Isonicotinic Acid ◽  
Structural Investigations ◽  
Mycolic Acids ◽  
Nicotinamide Mononucleotide ◽  
Catalase Peroxidase ◽  
Nicotinamide Coenzymes

ABSTRACT The antituberculosis drug isoniazid (INH) is quickly oxidized by stoichiometric amounts of manganese(III) pyrophosphate. In the presence of nicotinamide coenzymes (NAD+, NADH, nicotinamide mononucleotide [NMN+]) and nicotinic acid adenine dinucleotide (DNAD+), INH oxidation produced the formation of INH-coenzyme adducts in addition to known biologically inactive products (isonicotinic acid, isonicotinamide, and isonicotinaldehyde). A pool of INH-NAD(H) adducts preformed in solution allowed the rapid and strong inhibition of in vitro activity of the enoyl-acyl carrier protein reductase InhA, an INH target in the biosynthetic pathway of mycolic acids: the inhibition was 90 or 60% when the adducts were formed in the presence of NAD+ or NADH, respectively. Under similar conditions, no inhibitory activity of INH-NMN(H) and INH-DNAD(H) adducts was detected. When an isolated pool of 100 nM INH-NAD(H) adducts was first incubated with InhA, the enzyme activity was inhibited by 80%; when present in excess, both NADH and decenoyl-coenzyme A are able to prevent this phenomenon. InhA inhibition by several types of INH-coenzyme adducts coexisting in solution is discussed in relation with the structure of the coenzyme, the stereochemistry of the adducts, and their existence as both open and cyclic forms. Thus, manganese(III) pyrophosphate appears to be an efficient and convenient alternative oxidant to mimic the activity of the Mycobacterium tuberculosis KatG catalase-peroxidase and will be useful for further mechanistic studies of INH activation and for structural investigations of reactive INH species in order to promote the design of new inhibitors of InhA as potential antituberculous drugs.

scholarly journals In VitroandIn VivoActivities of the Nitroimidazole TBA-354 against Mycobacterium tuberculosis

2014 ◽  
Vol 59 (1) ◽  
pp. 136-144 ◽  
Author(s):  
A. M. Upton ◽  
S. Cho ◽  
T. J. Yang ◽  
Y. Kim ◽  
Y. Wang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Pharmacokinetic Profile ◽  
Multidrug Resistant ◽  
Phase Iii ◽  
Drug Resistant ◽  
Next Generation ◽  
Content Type ◽  
Resistant Tuberculosis

ABSTRACTNitroimidazoles are a promising new class of antitubercular agents. The nitroimidazo-oxazole delamanid (OPC-67683, Deltyba) is in phase III trials for the treatment of multidrug-resistant tuberculosis, while the nitroimidazo-oxazine PA-824 is entering phase III for drug-sensitive and drug-resistant tuberculosis. TBA-354 (SN31354[(S)-2-nitro-6-((6-(4-trifluoromethoxy)phenyl)pyridine-3-yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine]) is a pyridine-containing biaryl compound with exceptional efficacy against chronic murine tuberculosis and favorable bioavailability in preliminary rodent studies. It was selected as a potential next-generation antituberculosis nitroimidazole following an extensive medicinal chemistry effort. Here, we further evaluate the pharmacokinetic properties and activity of TBA-354 againstMycobacterium tuberculosis. TBA-354 is narrow spectrum and bactericidalin vitroagainst replicating and nonreplicatingMycobacterium tuberculosis, with potency similar to that of delamanid and greater than that of PA-824. The addition of serum protein or albumin does not significantly alter this activity. TBA-354 maintains activity againstMycobacterium tuberculosisH37Rv isogenic monoresistant strains and clinical drug-sensitive and drug-resistant isolates. Spontaneous resistant mutants appear at a frequency of 3 × 10−7.In vitrostudies andin vivostudies in mice confirm that TBA-354 has high bioavailability and a long elimination half-life.In vitrostudies suggest a low risk of drug-drug interactions. Low-dose aerosol infection models of acute and chronic murine tuberculosis reveal time- and dose-dependentin vivobactericidal activity that is at least as potent as that of delamanid and more potent than that of PA-824. Its superior potency and pharmacokinetic profile that predicts suitability for once-daily oral dosing suggest that TBA-354 be studied further for its potential as a next-generation nitroimidazole.

scholarly journals In vitro effects of quinine on the antibacterial activity of erythromycin against bacteria of clinical relevance

2021 ◽  
Vol 14 (2) ◽  
pp. 077-086
Author(s):  
Oluremi Adejoke Akinwale ◽  
Uyi Oluwatobi Emokpae ◽  
Opeyemi Mariam Adebogun ◽  
Morenike Olutumbi Adeoye-Isijola ◽  
Olufunmiso Olusola Olajuyigbe
Keyword(s):  
Antibacterial Activity ◽  
Synergistic Effect ◽  
Clinical Relevance ◽  
Bacterial Infections ◽  
Antibacterial Activities ◽  
Antibacterial Effects ◽  
Agar Dilution ◽  
Inhibition Zones ◽  
In Vitro Effects

The study investigated the in vitro effects of quinine on the antibacterial activity of erythromycin for possible interactions. The antibacterial activities of each drug and their combinations were investigated by agar diffusion, agar and macrobroth dilution methods. While 100 µl of 1000 µg/ml of erythromycin produced inhibition zones ranging between 13 and 31 ± 1.0 mm in all the isolates except K. pneumoniae and P. aeruginosa ATCC 19582, combining the highest concentration of erythromycin with 35 µg/ml of quinine produced inhibition zones ranging between 14 and 34 ± 1.0 mm with the exception of S. flexneri KZN. Though quinine had no antibacterial effects on the isolates, erythromycin was effective at minimum inhibitory concentrations (MICs) ranging between 25 and 100 µg/ml while their combinations resulted in reduction of MICs of most of the isolates to 12.5 µg/ml except those against A. calcaoceuticus anitratus CSIR, Ps. aeruginosa ATCC 15442, P. shigelloides ATCC 51903, A. hydrophila ATCC 35654, Ps. aeruginosa ATCC 19582 and E. faecalis KZN that remained unchanged in agar dilution. While the MICs of erythromycin ranged between 25 and 50 µg/ml, the MICs of this antibiotic was reduced to concentrations ranging between 12.5 and 50 µg/ml indicating 50% to 75% in the presence of quinine. The combination of erythromycin and quinine, in vitro, resulted in synergistic (50%), additive/indifference (44.44%) and antagonistic (11.11%) interactions while quinine at concentrations lower than plasma quinine concentrations was inhibitory to the antibacterial activity of erythromycin. The synergistic effect may serve as remedy for bacterial infections in which the test bacteria have been implicated.

scholarly journals In vitro and in vivo antibacterial activities of CS-940, a new 6-fluoro-8-difluoromethoxy quinolone.

1996 ◽  
Vol 40 (5) ◽  
pp. 1201-1207 ◽  
Author(s):  
N Masuda ◽  
Y Takahashi ◽  
M Otsuki ◽  
E Ibuki ◽  
H Miyoshi ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Oral Treatment ◽  
Horse Serum ◽  
Antibacterial Activities ◽  
Inoculum Size ◽  
The Other ◽  
Gram Positive Bacteria ◽  
Systemic Infections

The in vitro and in vivo activities of CS-940, a new 6-fluoro-8-difluoromethoxy quinolone, were compared with those of ciprofloxacin, tosufloxacin, sparfloxacin, and levofloxacin. The in vitro activity of CS-940 against gram-positive bacteria was nearly equal to or greater than those of the other quinolones tested. In particular, CS-940 was two to eight times more active against methicillin-resistant Staphylococcus aureus than the other quinolones, at the MIC at which 90% of the clinical isolates are inhibited. Against gram-negative bacteria, the activity of CS-940 was comparable to or greater than those of tosufloxacin, sparfloxacin, and levofloxacin, while it was lower than that of ciprofloxacin. The activity of CS-940 was largely unaffected by medium, inoculum size, or the addition of horse serum, but it was decreased under acidic conditions, as was also seen with the other quinolones tested. CS-940 showed potent bactericidal activity against S. aureus, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. In oral treatment of mouse systemic infections caused by S. aureus, Streptococcus pneumoniae, Streptococcus pyogenes, E. coli, K. pneumoniae, Serratia marcescens, and P. aeruginosa, CS-940 was more effective than ciprofloxacin, sparfloxacin, and levofloxacin against all strains tested. Against experimental pneumonia with K. pneumoniae in mice, CS-940 was the most effective of all the quinolones tested. These results suggest that CS-940 may be effective in the therapy of various bacterial infections.

scholarly journals Mode of Action of Kanglemycin A, an Ansamycin Natural Product that Is Active against Rifampicin-Resistant Mycobacterium tuberculosis

2018 ◽  
Vol 72 (2) ◽  
pp. 263-274.e5 ◽  
Author(s):  
Hamed Mosaei ◽  
Vadim Molodtsov ◽  
Bernhard Kepplinger ◽  
John Harbottle ◽  
Christopher William Moon ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Natural Product ◽  
Mode Of Action

scholarly journals An Amphipathic Undecapeptide with All d-Amino Acids Shows Promising Activity against Colistin-Resistant Strains of Acinetobacter baumannii and a Dual Mode of Action

2015 ◽  
Vol 60 (1) ◽  
pp. 592-599 ◽  
Author(s):  
Alberto Oddo ◽  
Thomas T. Thomsen ◽  
Susanne Kjelstrup ◽  
Ciara Gorey ◽  
Henrik Franzyk ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Mode Of Action ◽  
Acquired Resistance ◽  
Antibacterial Activities ◽  
The Novel ◽  
Human Pathogens ◽  
Content Type ◽  
Resistant Strains ◽  
Multiple Strains

ABSTRACTMultiple strains ofAcinetobacter baumanniihave developed multidrug resistance (MDR), leaving colistin as the only effective treatment. The cecropin-α–melittin hybrid BP100 (KKLFKKILKYL-NH2) and its analogs have previously shown activity against a wide array of plant and human pathogens. In this study, we investigated thein vitroantibacterial activities of 18 BP100 analogs (four known and 14 new) against the MDRA. baumanniistrain ATCC BAA-1605, as well as against a number of other clinically relevant human pathogens. Selected peptides were further evaluated against strains ofA. baumanniithat acquired resistance to colistin due to mutations of thelpxC,lpxD,pmrA, andpmrBgenes. The novel analogue BP214 showed antimicrobial activity at 1 to 2 μM and a hemolytic 50% effective concentration (EC50) of >150 μM. The lower activity of its enantiomer suggests a dual, specific and nonspecific mode of action. Interestingly, colistin behaved antagonistically to BP214 whenpmrABandlpxCmutants were challenged.

scholarly journals The Herbicide Saflufenacil (Kixor™) is a New Inhibitor of Protoporphyrinogen IX Oxidase Activity

Weed Science ◽  
2010 ◽  
Vol 58 (1) ◽  
pp. 1-9 ◽  
Author(s):  
Klaus Grossmann ◽  
Ricarda Niggeweg ◽  
Nicole Christiansen ◽  
Ralf Looser ◽  
Thomas Ehrhardt
Keyword(s):  
Mode Of Action ◽  
Metabolite Profiling ◽  
Biosynthetic Pathway ◽  
Protoporphyrin Ix ◽  
Leaf Tissue ◽  
In Planta ◽  
Black Nightshade ◽  
Initial Characterization ◽  
Chemical Class

Saflufenacil (Kixor™) is a new herbicide of the pyrimidinedione chemical class for preplant burndown and selective preemergence dicot weed control in multiple crops, including corn. In this study, the mode of action of saflufenacil was investigated. For initial characterization, a series of biotests was used in a physionomics approach for comprehensive physiological profiling of saflufenacil effects. With the use of treated duckweed plants, metabolite profiling was performed based on quantification of metabolite changes, relative to untreated controls. Physiological and metabolite profiling suggested a mode of action similar to inhibitors of protoporphyrinogen IX oxidase (PPO) in tetrapyrrole biosynthetic pathway. Saflufenacil inhibited PPO enzyme activity in vitro with 50% inhibition of 0.4 nM for the enzymes isolated from black nightshade, velvetleaf, and corn. PPO inhibition by saflufenacil caused accumulations of protoporphyrin IX (Proto) and hydrogen peroxide (H2O2) in leaf tissue of black nightshade and velvetleaf. In corn, only slight increases in Proto and H2O2 were found, which reflects in planta tolerance of this crop. The results show that saflufenacil is a new PPO-inhibiting, peroxidizing herbicide.

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