scholarly journals Development of Methionyl-tRNA Synthetase Inhibitors as Antibiotics for Gram-Positive Bacterial Infections

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Omeed Faghih ◽  
Zhongsheng Zhang ◽  
Ranae M. Ranade ◽  
J. Robert Gillespie ◽  
Sharon A. Creason ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Bacterial Species ◽  
Bacterial Load ◽  
Trna Synthetase ◽  
Resistant Bacteria ◽  
Gram Positive ◽  
Gram Negative ◽  
Content Type ◽  
Gram Positive Bacteria ◽  
Methionyl Trna Synthetase

ABSTRACT Antibiotic-resistant bacteria are widespread and pose a growing threat to human health. New antibiotics acting by novel mechanisms of action are needed to address this challenge. The bacterial methionyl-tRNA synthetase (MetRS) enzyme is essential for protein synthesis, and the type found in Gram-positive bacteria is substantially different from its counterpart found in the mammalian cytoplasm. Both previously published and new selective inhibitors were shown to be highly active against Gram-positive bacteria with MICs of ≤1.3 μg/ml against Staphylococcus, Enterococcus, and Streptococcus strains. Incorporation of radioactive precursors demonstrated that the mechanism of activity was due to the inhibition of protein synthesis. Little activity against Gram-negative bacteria was observed, consistent with the fact that Gram-negative bacterial species contain a different type of MetRS enzyme. The ratio of the MIC to the minimum bactericidal concentration (MBC) was consistent with a bacteriostatic mechanism. The level of protein binding of the compounds was high (>95%), and this translated to a substantial increase in MICs when the compounds were tested in the presence of serum. Despite this, the compounds were very active when they were tested in a Staphylococcus aureus murine thigh infection model. Compounds 1717 and 2144, given by oral gavage, resulted in 3- to 4-log decreases in the bacterial load compared to that in vehicle-treated mice, which was comparable to the results observed with the comparator drugs, vancomycin and linezolid. In summary, the research describes MetRS inhibitors with oral bioavailability that represent a class of compounds acting by a novel mechanism with excellent potential for clinical development.

scholarly journals Molecular Characterization of Zinc (Zn) Resistant Bacteria in Banger River, Pekalongan, Indonesia

2018 ◽  
Vol 10 (3) ◽  
pp. 622-628
Author(s):  
Fitri Arum Sasi ◽  
Hermin Pancasakti Kusumaningrum ◽  
Anto Budiharjo
Keyword(s):  
Bacterial Species ◽  
Selective Medium ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Gram Positive ◽  
Gram Negative ◽  
Indigenous Bacteria ◽  
Gram Positive Bacteria ◽  
Sequences Analysis

Indigenous bacteria are able to remove the metals contamination in environment. This study aimed to assess the resistance of bacterial species to Zinc (Zn) in Banger River, Pekalongan City. The bacteria from three different parts of Banger River were isolated and inoculated in Zn-selective medium. Then, molecular identification to determine the bacteria species was conducted using polymerase chain reaction (PCR) by applying forward-reverse 16SrRNA gene primers. The sequences analysis was conducted using MUSCLE and MEGA6. There were seven dominant species that possibly resistant to Zn. Approximately, every isolate could reach more than 95 % from 2000 ppm of Zn in the medium. The higher absorption of Zn was found in Z5 isolate. The seven bacteria species were clustered into nine genera i.e. Klebsiela, Xenorhabdus, Cronobacter, Enterobacter, Escherichia, Shigella and Sporomusa known as Gram Negative bacteria and Clostridium and Bacillus as Gram Positive bacteria. In Gram Positive bacteria, especially Bacillus sp, carboxyl group in peptidoglycan play a role as metal binder. In Gram-negative bacteria, lipopolysaccharide (LPS) which is highly anionic component on the outer membrane, able to catch the Zn. Besides that, Enterobacter activates endogen antioxidants such as glutathione peroxidase (GSHPx), glutathione reductase (GR), catalase (CAT) and superoxide dismutase (SOD). The research found there was possible seven novel indigenous bacteria species in Banger that able to remove Zn from the sediment extremely. This finding can be developed as an eco-friendly approach to reduce metals pollution using local microorganisms.

scholarly journals Nybomycin Inhibits both Fluoroquinolone-Sensitive and Fluoroquinolone-Resistant Escherichia coli DNA Gyrase

2021 ◽  
Vol 65 (5) ◽  
Author(s):  
Dmitrii I. Shiriaev ◽  
Alina A. Sofronova ◽  
Ekaterina A. Berdnikovich ◽  
Dmitrii A. Lukianov ◽  
Ekaterina S. Komarova ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Bacterial Species ◽  
Dna Gyrase ◽  
Resistant Bacteria ◽  
Mutant Form ◽  
Wild Type ◽  
Topoisomerase Iv ◽  
Gram Positive ◽  
Gram Negative ◽  
Content Type

ABSTRACT Bacterial type II topoisomerases, DNA gyrase and topoisomerase IV, are targets of many antibiotics, including fluoroquinolones (FQs). Unfortunately, a number of bacterial species easily acquire resistance to FQs by mutations in either DNA gyrase or topoisomerase IV genes. The emergence of resistant pathogenic strains is a global problem in health care; therefore, identifying alternative pathways to thwart their persistence is the current frontier in drug discovery. Nybomycins are an attractive class of compounds, reported to be “reverse antibiotics” that selectively inhibit growth of some Gram-positive FQ-resistant bacteria by targeting the mutant form of DNA gyrase while being inactive against wild-type strains with FQ-sensitive gyrases. The strong “reverse” effect was demonstrated only for a few Gram-positive organisms resistant to FQs due to the S83L/I mutation in the GyrA subunit of DNA gyrase. However, the activity of nybomycins has not been extensively explored among Gram-negative species. Here, we observed that in a ΔtolC strain of the Gram-negative Escherichia coli with enhanced permeability, wild-type gyrase and a GyrA S83L mutant, resistant to fluoroquinolones, are similarly sensitive to nybomycin.

scholarly journals BioSAXS measurements reveal that two antimicrobial peptides induce similar molecular changes in Gram-negative and Gram-positive bacteria

2019 ◽  
Author(s):  
A.R. von Gundlach ◽  
M. Ashby ◽  
J. Gani ◽  
P. M. Lopez-Perez ◽  
A. Cookson ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Mode Of Action ◽  
Bacterial Load ◽  
Ultrastructural Changes ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Gram Positive ◽  
Gram Negative ◽  
E Coli ◽  
Gram Positive Bacteria

AbstractTwo highly active short broad-spectrum AMPs (14D and 69D) with unknown mode of action have been investigated in regards to their effect against the Gram-negative bacteriaE. coliand the Gram-positive bacteria methicillin-resistantStaphylococcus aureus(MRSA). Minimal inhibitory concentration (MIC) measurements using a cell density of 108cfu/ml resulted in values between 16 and 32 μg/ml. Time kill experiments using 108cfu/ml revealed complete killing, except for 69D in combination with MRSA, where bacterial load was reduced a million times. Small angle X-ray scattering of biological samples (BioSAXS) at 108cfu/ml was applied to investigate the ultrastructural changes inE. coliand MRSA in response to these two broad-spectrum AMPs. In addition, electron microscopy (EM) was performed to visualize the treated and non-treated bacteria. As expected, the scattering curves generated using BioSAXS show the ultrastructure of the Gram-positive and Gram-negative bacteria to be very different (BioSAXS is not susceptible to the outer shape). After treatment with either peptide, the scattering curves ofE. coliand MRSA cells are much more alike. This data in conjunction with the EM indicates that ribosomes might be effected by the treatment as well as changes in the nucleoid occurs. Whereas in EM it is notoriously difficult to observe changes for spherical Gram-positives, the BioSAXS results are superior and reveal strongly similar effects for both peptides induced in Gram-positive as well as Gram-negative bacteria. Given the high-throughput possibility and robust statistics BioSAXS can support and speed up mode of action research in AMPs and other antimicrobial compounds, making a contribution towards the development of urgently needed drugs against resistant bacteria.

scholarly journals Increasing the Antimicrobial Activity of Nisin-Based Lantibiotics against Gram-Negative Pathogens

2018 ◽  
Vol 84 (12) ◽  
Author(s):  
Qian Li ◽  
Manuel Montalban-Lopez ◽  
Oscar P. Kuipers
Keyword(s):  
Antimicrobial Peptides ◽  
Outer Membrane ◽  
Rational Design ◽  
Bacterial Species ◽  
Gram Negative Bacteria ◽  
Gram Positive ◽  
Gram Negative ◽  
Content Type ◽  
Gram Positive Bacteria ◽  
Lipid Ii

ABSTRACTLantibiotics are ribosomally synthesized and posttranslationally modified antimicrobial compounds containing lanthionine and methyl-lanthionine residues. Nisin, one of the most extensively studied and used lantibiotics, has been shown to display very potent activity against Gram-positive bacteria, and stable resistance is rarely observed. By binding to lipid II and forming pores in the membrane, nisin can cause the efflux of cellular constituents and inhibit cell wall biosynthesis. However, the activity of nisin against Gram-negative bacteria is much lower than that against Gram-positive bacteria, mainly because lipid II is located at the inner membrane, and the rather impermeable outer membrane in Gram-negative bacteria prevents nisin from reaching lipid II. Thus, if the outer membrane-traversing efficiency of nisin could be increased, the activity against Gram-negative bacteria could, in principle, be enhanced. In this work, several relatively short peptides with activity against Gram-negative bacteria were selected from literature data to be fused as tails to the C terminus of either full or truncated nisin species. Among these, we found that one of three tails (tail 2 [T2; DKYLPRPRPV], T6 [NGVQPKY], and T8 [KIAKVALKAL]) attached to a part of nisin displayed improved activity against Gram-negative microorganisms. Next, we rationally designed and reengineered the most promising fusion peptides. Several mutants whose activity significantly outperformed that of nisin against Gram-negative pathogens were obtained. The activity of the tail 16 mutant 2 (T16m2) construct against several important Gram-negative pathogens (i.e.,Escherichia coli,Klebsiella pneumoniae,Acinetobacter baumannii,Pseudomonas aeruginosa,Enterobacter aerogenes) was increased 4- to 12-fold compared to that of nisin. This study indicates that the rational design of nisin can selectively and significantly improve its outer membrane-permeating capacity as well as its activity against Gram-negative pathogens.IMPORTANCELantibiotics are antimicrobial peptides that are highly active against Gram-positive bacteria but that have relatively poor activity against most Gram-negative bacteria. Here, we modified the model lantibiotic nisin by fusing parts of it to antimicrobial peptides with known activity against Gram-negative bacteria. The appropriate selection of peptidic moieties that could be attached to (parts of) nisin could lead to a significant increase in its inhibitory activity against Gram-negative bacteria. Using this strategy, hybrids that outperformed nisin by displaying 4- to 12-fold higher levels of activity against relevant Gram-negative bacterial species were produced. This study shows the power of modified peptide engineering to alter target specificity in a desired direction.

Microbiological pattern of prosthetic hip and knee infections: a high-volume, single-centre experience in China

2021 ◽  
Author(s):  
Yali Yu ◽  
Yiyi Kong ◽  
Jing Ye ◽  
Aiguo Wang ◽  
Wenteng Si
Keyword(s):  
Antibiotic Treatment ◽  
Prolonged Treatment ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Gram Positive ◽  
Musculoskeletal Infection ◽  
Gram Negative ◽  
Content Type ◽  
Empirical Antibiotic Treatment ◽  
Link Type

Introduction. Prosthetic joint infection (PJI) is a serious complication after arthroplasty, which results in high morbidity, prolonged treatment and considerable healthcare expenses in the absence of accurate diagnosis. In China, microbiological data on PJIs are still scarce. Hypothesis/Gap Statement. The incidence of PJI is increasing year by year, and the proportion of drug-resistant bacteria infection is nicreasing, which brings severe challenges to the treatment of infection. Aim. This study aimed to identify the pathogens in PJIs, multi-drug resistance, and evaluate the effect of the treatment regimen in patients with PJI. Methodology. A total of 366 consecutive cases of PJI in the hip or knee joint were admitted at the Orthopedic Surgery Center in Zhengzhou, China from January 2012 to December 2018. Infections were confirmed in accordance with the Infectious Diseases Society of America and the Musculoskeletal Infection Society (MSIS) criteria. Concurrently, patient demographic data, incidence and antibiotic resistance were investigated. Statistical differences were analysed using Fisher’s exact test or chi-square test. Results. Altogether, 318 PJI cases satisfying the inclusion criteria were enrolled in this study, including 148 with hip PJIs and 170 with knee PJIs. The average age of patients with hip PJIs was lesser than that of patients with knee PJIs (56.4 vs. 68.6 years). Meanwhile, coagulase-negative staphylococcus (CNS, n=81, 25.5 %) was the predominant causative pathogen, followed by Staphylococcus aureus (n=67, 21.1 %). Methicillin-resistant Staphylococcus (MRS) was identified in 28.9 % of PJI patients. In addition, fungus accounted for 4.8 % (n=15), non-tuberculosis mycobacterium accounted for 1.6 % (n=5), polymicrobial pathogens accounted for 21.7 % (n=69), and Gram-negative bacteria accounted for 7.9 % (n=25) of the total infections. The results of antibiotic susceptibility testing showed that gentamicin and clindamycin β-lactam antibiotics were poorly susceptible to Gram-positive isolates, but they were sensitive to rifampicin, linezolid and vancomycin. While antibiotics such as amikacin and imipenem were effective against Gram-negative bacteria, there was a high resistance rate of other pathogens to gentamicin, clindamycin and some quinolone antibacterial drugs. Empirical antibiotic treatment should combine vancomycin and cephalosporin, levofloxacin or clindamycin. When the pathogen is confirmed, the treatment should be individualized. Conclusions. The prevalence of culture-negative PJIs is still very high. Gram-positive bacteria are still the main type of pathogens that cause PJIs. Attention should be paid to the high incidence of MRS, such as MRSA and MR-CNS, among PJI patients. Empirical antibiotic treatment should cover Gram-positive isolates, especially Staphylococcus .

scholarly journals Sarconesin II, a New Antimicrobial Peptide Isolated from Sarconesiopsis magellanica Excretions and Secretions

Molecules ◽  
2019 ◽  
Vol 24 (11) ◽  
pp. 2077 ◽  
Author(s):  
Andrea Díaz-Roa ◽  
Abraham Espinoza-Culupú ◽  
Orlando Torres-García ◽  
Monamaris M. Borges ◽  
Ivan N. Avino ◽  
...  
Keyword(s):  
Micrococcus Luteus ◽  
Multidrug Resistant ◽  
Peptide Sequence ◽  
Resistant Bacteria ◽  
Gram Positive ◽  
Antimicrobial Drugs ◽  
Gram Negative ◽  
Gram Positive Bacteria ◽  
Conserved Domain ◽  
Health Institutions

Antibiotic resistance is at dangerous levels and increasing worldwide. The search for new antimicrobial drugs to counteract this problem is a priority for health institutions and organizations, both globally and in individual countries. Sarconesiopsis magellanica blowfly larval excretions and secretions (ES) are an important source for isolating antimicrobial peptides (AMPs). This study aims to identify and characterize a new S. magellanica AMP. RP-HPLC was used to fractionate ES, using C18 columns, and their antimicrobial activity was evaluated. The peptide sequence of the fraction collected at 43.7 min was determined by mass spectrometry (MS). Fluorescence and electronic microscopy were used to evaluate the mechanism of action. Toxicity was tested on HeLa cells and human erythrocytes; physicochemical properties were evaluated. The molecule in the ES was characterized as sarconesin II and it showed activity against Gram-negative (Escherichia coli MG1655, Pseudomonas aeruginosa ATCC 27853, P. aeruginosa PA14) and Gram-positive (Staphylococcus aureus ATCC 29213, Micrococcus luteus A270) bacteria. The lowest minimum inhibitory concentration obtained was 1.9 μM for M. luteus A270; the AMP had no toxicity in any cells tested here and its action in bacterial membrane and DNA was confirmed. Sarconesin II was documented as a conserved domain of the ATP synthase protein belonging to the Fli-1 superfamily. The data reported here indicated that peptides could be alternative therapeutic candidates for use in infections against Gram-negative and Gram-positive bacteria and eventually as a new resource of compounds for combating multidrug-resistant bacteria.

scholarly journals Inhibition of Methionyl-tRNA Synthetase by REP8839 and Effects of Resistance Mutations on Enzyme Activity

2008 ◽  
Vol 53 (1) ◽  
pp. 86-94 ◽  
Author(s):  
Louis S. Green ◽  
James M. Bullard ◽  
Wendy Ribble ◽  
Frank Dean ◽  
David F. Ayers ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Mechanistic Explanation ◽  
Trna Synthetase ◽  
Turnover Rates ◽  
Wild Type ◽  
Resistance Mutations ◽  
Gram Positive ◽  
Gram Positive Bacteria ◽  
Human Orthologs ◽  
Methionyl Trna Synthetase

ABSTRACT REP8839 is a selective inhibitor of methionyl-tRNA synthetase (MetRS) with antibacterial activity against a variety of gram-positive organisms. We determined REP8839 potency against Staphylococcus aureus MetRS and assessed its selectivity for bacterial versus human orthologs of MetRS. The inhibition constant (Ki ) of REP8839 was 10 pM for Staphylococcus aureus MetRS. Inhibition of MetRS by REP8839 was competitive with methionine and uncompetitive with ATP. Thus, high physiological ATP levels would actually facilitate optimal binding of the inhibitor. While many gram-positive bacteria, such as Staphylococcus aureus, express exclusively the MetRS1 subtype, many gram-negative bacteria express an alternative homolog called MetRS2. Some gram-positive bacteria, such as Streptococcus pneumoniae and Bacillus anthracis, express both MetRS1 and MetRS2. MetRS2 orthologs were considerably less susceptible to REP8839 inhibition. REP8839 inhibition of human mitochondrial MetRS was 1,000-fold weaker than inhibition of Staphylococcus aureus MetRS; inhibition of human cytoplasmic MetRS was not detectable, corresponding to >1,000,000-fold selectivity for the bacterial target relative to its cytoplasmic counterpart. Mutations in MetRS that confer reduced susceptibility to REP8839 were examined. The mutant MetRS enzymes generally exhibited substantially impaired catalytic activity, particularly in aminoacylation turnover rates. REP8839 Ki values ranged from 4- to 190,000-fold higher for the mutant enzymes than for wild-type MetRS. These observations provide a potential mechanistic explanation for the reduced growth fitness observed with MetRS mutant strains relative to that with wild-type Staphylococcus aureus.

scholarly journals In VitroActivity of AZD0914, a Novel Bacterial DNA Gyrase/Topoisomerase IV Inhibitor, against Clinically Relevant Gram-Positive and Fastidious Gram-Negative Pathogens

2015 ◽  
Vol 59 (10) ◽  
pp. 6053-6063 ◽  
Author(s):  
Douglas J. Biedenbach ◽  
Michael D. Huband ◽  
Meredith Hackel ◽  
Boudewijn L. M. de Jonge ◽  
Daniel F. Sahm ◽  
...  
Keyword(s):  
Bacterial Species ◽  
Dna Gyrase ◽  
Species Group ◽  
Coagulase Negative Staphylococci ◽  
Topoisomerase Iv ◽  
Gram Positive ◽  
Bacterial Dna ◽  
Gram Negative ◽  
Content Type

ABSTRACTAZD0914, a new spiropyrimidinetrione bacterial DNA gyrase inhibitor with a novel mode of inhibition, has activity against bacterial species commonly cultured from patient infection specimens, including fluoroquinolone-resistant isolates. This study assessed thein vitroactivity of AZD0914 against key Gram-positive and fastidious Gram-negative clinical isolates collected globally in 2013. AZD0914 demonstrated potent activity, with MIC90s for AZD0914 of 0.25 mg/liter againstStaphylococcus aureus(n= 11,680), coagulase-negative staphylococci (n= 1,923), streptococci (n= 4,380), andMoraxella catarrhalis(n= 145), 0.5 mg/liter againstStaphylococcus lugdunensis(n= 120) andHaemophilus influenzae(n= 352), 1 mg/liter againstEnterococcus faecalis(n= 1,241), and 2 mg/liter againstHaemophilus parainfluenzae(n= 70). The activity againstEnterococcus faeciumwas more limited (MIC90, 8 mg/liter). The spectrum and potency of AZD0914 included fluoroquinolone-resistant isolates in each species group, including methicillin-resistant staphylococci, penicillin-resistant streptococci, vancomycin-resistant enterococci, β-lactamase-producingHaemophilusspp., andM. catarrhalis. Based on thesein vitrofindings, AZD0914 warrants further investigation for its utility against a variety of Gram-positive and fastidious Gram-negative bacterial species.

scholarly journals Recognition of Streptococcus pneumoniae and Muramyl Dipeptide by NOD2 Results in Potent Induction of MMP-9, Which Can Be Controlled by Lipopolysaccharide Stimulation

2014 ◽  
Vol 82 (12) ◽  
pp. 4952-4958 ◽  
Author(s):  
Marloes Vissers ◽  
Yvonne Hartman ◽  
Laszlo Groh ◽  
Dirk J. de Jong ◽  
Marien I. de Jonge ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Mononuclear Cells ◽  
Muramyl Dipeptide ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Gram Negative Bacteria ◽  
Gram Positive ◽  
Potent Inducer ◽  
Gram Negative ◽  
Content Type ◽  
Gram Positive Bacteria

ABSTRACTMatrix metallopeptidase 9 (MMP-9) is a protease involved in the degradation of extracellular matrix collagen. Evidence suggests that MMP-9 is involved in pathogenesis duringStreptococcus pneumoniaeinfection. However, not much is known about the induction of MMP-9 and the regulatory processes involved. We show here that the Gram-positive bacteria used in this study induced large amounts of MMP-9, in contrast to the Gram-negative bacteria that were used. An important pathogen-associated molecular pattern (PAMP) for Gram-positive bacteria is muramyl dipeptide (MDP). MDP is a very potent inducer of MMP-9 and showed a dose-dependent MMP-9 induction. Experiments using peripheral blood mononuclear cells (PBMCs) from Crohn's disease patients with nonfunctional NOD2 showed that MMP-9 induction byStreptococcus pneumoniaeand MDP is NOD2 dependent. Increasing amounts of lipopolysaccharide (LPS), an important PAMP for Gram-negative bacteria, resulted in decreasing amounts of MMP-9. Moreover, the induction of MMP-9 by MDP could be counteracted by simultaneously adding LPS. The inhibition of MMP-9 expression by LPS was found to be regulated posttranscriptionally, independently of tissue inhibitor of metalloproteinase 1 (TIMP-1), an endogenous inhibitor of MMP-9. Collectively, these data show thatStreptococcus pneumoniaeis able to induce large amounts of MMP-9. These high MMP-9 levels are potentially involved inStreptococcus pneumoniaepathogenesis.

scholarly journals In VitroAntibacterial Activity of AZD0914, a New Spiropyrimidinetrione DNA Gyrase/Topoisomerase Inhibitor with Potent Activity against Gram-Positive, Fastidious Gram-Negative, and Atypical Bacteria

2014 ◽  
Vol 59 (1) ◽  
pp. 467-474 ◽  
Author(s):  
Michael D. Huband ◽  
Patricia A. Bradford ◽  
Linda G. Otterson ◽  
Gregory S. Basarab ◽  
Amy C. Kutschke ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Legionella Pneumophila ◽  
Bacterial Species ◽  
Dna Gyrase ◽  
Cross Resistance ◽  
Gram Positive ◽  
Gram Negative ◽  
Content Type ◽  
Topoisomerase Inhibitor

ABSTRACTAZD0914 is a new spiropyrimidinetrione bacterial DNA gyrase/topoisomerase inhibitor with potentin vitroantibacterial activity against key Gram-positive (Staphylococcus aureus,Staphylococcus epidermidis,Streptococcus pneumoniae,Streptococcus pyogenes, andStreptococcus agalactiae), fastidious Gram-negative (Haemophilus influenzaeandNeisseria gonorrhoeae), atypical (Legionella pneumophila), and anaerobic (Clostridium difficile) bacterial species, including isolates with known resistance to fluoroquinolones. AZD0914 works via inhibition of DNA biosynthesis and accumulation of double-strand cleavages; this mechanism of inhibition differs from those of other marketed antibacterial compounds. AZD0914 stabilizes and arrests the cleaved covalent complex of gyrase with double-strand broken DNA under permissive conditions and thus blocks religation of the double-strand cleaved DNA to form fused circular DNA. Whereas this mechanism is similar to that seen with fluoroquinolones, it is mechanistically distinct. AZD0914 exhibited low frequencies of spontaneous resistance inS. aureus, and if mutants were obtained, the mutations mapped togyrB. Additionally, no cross-resistance was observed for AZD0914 against recent bacterial clinical isolates demonstrating resistance to fluoroquinolones or other drug classes, including macrolides, β-lactams, glycopeptides, and oxazolidinones. AZD0914 was bactericidal in both minimum bactericidal concentration andin vitrotime-kill studies. Inin vitrocheckerboard/synergy testing with 17 comparator antibacterials, only additivity/indifference was observed. The potentin vitroantibacterial activity (including activity against fluoroquinolone-resistant isolates), low frequency of resistance, lack of cross-resistance, and bactericidal activity of AZD0914 support its continued development.

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