COMPLEX FORMATION BETWEEN BASIC ANTIBIOTICS AND DEOXYRIBONUCLEIC ACID IN HUMAN PULMONARY SECRETIONS

PEDIATRICS ◽  
1965 ◽  
Vol 36 (5) ◽  
pp. 714-720
Author(s):  
Joseph L. Potter ◽  
LeRoy W. Matthews ◽  
Samuel Spector ◽  
Joy Lemm
Keyword(s):  
Cystic Fibrosis ◽  
Sodium Chloride ◽  
Complex Formation ◽  
Chain Length ◽  
Deoxyribonucleic Acid ◽  
Antimicrobial Agents ◽  
Dnase I ◽  
Two Samples

1. Complex formation and precipitation of DNA by neomycin, with consequent inactivation of the antibiotic, has been shown to occur in the pulmonary secretions of patients with cystic fibrosis. 2. Highly polymerized DNA from a variety of sources, as well as two samples of RNA, were precipitated by neomycin in vitro. Polymixin, kanamycin, colymycin, and streptomycin similarly co-precipitate with DNA in vitro. 3. The minimum chain length of polynucleotide required for precipitation in the DNA-neomycin system was 10. 4. The complex is readily attacked by DNase I resulting in the splitting of the DNA and the liberation of the antibiotic. Both components of the complex are solubilized in M sodium chloride. 5. The resistance of purulent foci of infection to therapy with basic antimicrobial agents may, in part, be due to the complex formation with the high levels of DNA found at the site of infection.

scholarly journals The Oxazolidinone Linezolid Inhibits Initiation of Protein Synthesis in Bacteria

1998 ◽  
Vol 42 (12) ◽  
pp. 3251-3255 ◽  
Author(s):  
Steve M. Swaney ◽  
Hiroyuki Aoki ◽  
M. Clelia Ganoza ◽  
Dean L. Shinabarger
Keyword(s):  
Protein Synthesis ◽  
Complex Formation ◽  
Antimicrobial Agents ◽  
Ribosomal Subunit ◽  
Multidrug Resistant ◽  
Binary Complex ◽  
Initiation Complex ◽  
Ribosomal Subunits ◽  
Bacterial Translation

ABSTRACT The oxazolidinones represent a new class of antimicrobial agents which are active against multidrug-resistant staphylococci, streptococci, and enterococci. Previous studies have demonstrated that oxazolidinones inhibit bacterial translation in vitro at a step preceding elongation but after the charging ofN-formylmethionine to the initiator tRNA molecule. The event that occurs between these two steps is termed initiation. Initiation of protein synthesis requires the simultaneous presence of N-formylmethionine-tRNA, the 30S ribosomal subunit, mRNA, GTP, and the initiation factors IF1, IF2, and IF3. An initiation complex assay measuring the binding of [3H]N-formylmethionyl-tRNA to ribosomes in response to mRNA binding was used in order to investigate the mechanism of oxazolidinone action. Linezolid inhibited initiation complex formation with either the 30S or the 70S ribosomal subunits fromEscherichia coli. In addition, complex formation withStaphylococcus aureus 70S tight-couple ribosomes was inhibited by linezolid. Linezolid did not inhibit the independent binding of either mRNA or N-formylmethionyl-tRNA toE. coli 30S ribosomal subunits, nor did it prevent the formation of the IF2–N-formylmethionyl-tRNA binary complex. The results demonstrate that oxazolidinones inhibit the formation of the initiation complex in bacterial translation systems by preventing formation of theN-formylmethionyl-tRNA–ribosome–mRNA ternary complex.

Activities of Tobramycin and Six Other Antibiotics against Pseudomonas aeruginosa Isolates from Patients with Cystic Fibrosis

1999 ◽  
Vol 43 (12) ◽  
pp. 2877-2880 ◽  
Author(s):  
Ribhi M. Shawar ◽  
David L. MacLeod ◽  
Richard L. Garber ◽  
Jane L. Burns ◽  
Jenny R. Stapp ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Antimicrobial Agents ◽  
Active Drug ◽  
Resistance Mechanisms ◽  
Phase Iii ◽  
In Vitro Activity ◽  
Phase Iii Clinical Trials ◽  
Multiple Antibiotics

ABSTRACT The in vitro activity of tobramycin was compared with those of six other antimicrobial agents against 1,240 Pseudomonas aeruginosa isolates collected from 508 patients with cystic fibrosis during pretreatment visits as part of the phase III clinical trials of tobramycin solution for inhalation. The tobramycin MIC at which 50% of isolates are inhibited (MIC50) and MIC90 were 1 and 8 μg/ml, respectively. Tobramycin was the most active drug tested and also showed good activity against isolates resistant to multiple antibiotics. The isolates were less frequently resistant to tobramycin (5.4%) than to ceftazidime (11.1%), aztreonam (11.9%), amikacin (13.1%), ticarcillin (16.7%), gentamicin (19.3%), or ciprofloxacin (20.7%). For all antibiotics tested, nonmucoid isolates were more resistant than mucoid isolates. Of 56 isolates for which the tobramycin MIC was ≥16 μg/ml and that were investigated for resistance mechanisms, only 7 (12.5%) were shown to possess known aminoglycoside-modifying enzymes; the remaining were presumably resistant by an incompletely understood mechanism often referred to as “impermeability.”

scholarly journals In Vitro Activities of β-Lactam–β-Lactamase Inhibitor Antimicrobial Agents against Cystic Fibrosis Respiratory Pathogens

2019 ◽  
Vol 64 (1) ◽  
Author(s):  
Lindsay J. Caverly ◽  
Theodore Spilker ◽  
Linda M. Kalikin ◽  
Terri Stillwell ◽  
Carol Young ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Antimicrobial Agents ◽  
Multidrug Resistant ◽  
Respiratory Pathogens ◽  
Content Type ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Increased Activity ◽  
Lactamase Inhibitor

ABSTRACT We tested the in vitro activities of ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, piperacillin-tazobactam, and 11 other antimicrobial agents against 420 Burkholderia, Achromobacter, Stenotrophomonas, and Pandoraea strains, 89% of which were cultured from respiratory specimens from persons with cystic fibrosis. Among the β-lactam–β-lactamase inhibitor agents, meropenem-vaborbactam had the greatest activity against Burkholderia and Achromobacter, including multidrug-resistant and extensively-drug-resistant strains. None of the newer β-lactam–β-lactamase combination drugs showed increased activity compared to that of the older agents against Stenotrophomonas maltophilia or Pandoraea spp.

scholarly journals The Anti-Pseudomonal Peptide D-BMAP18 Is Active in Cystic Fibrosis Sputum and Displays Anti-Inflammatory In Vitro Activity

2020 ◽  
Vol 8 (9) ◽  
pp. 1407
Author(s):  
Margherita Degasperi ◽  
Chiara Agostinis ◽  
Mario Mardirossian ◽  
Massimo Maschio ◽  
Andrea Taddio ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Dnase I ◽  
Starting Point ◽  
Tnf Α ◽  
Specific Cytotoxicity ◽  
Ifn Γ ◽  
Lung Infections ◽  
Anti Inflammatory

Most Cystic Fibrosis (CF) patients succumb to airway inflammation and pulmonary infections due to Pseudomonas aeruginosa. D-BMAP18, a membrane-permeabilizing antimicrobial peptide composed of D-amino acids, was evaluated as a possible antibacterial aimed to address this issue. The antipseudomonal activity of D-BMAP18 was tested in a pathophysiological context. The peptide displayed activity against CF isolates of Pseudomonas aeruginosa in the presence of CF sputum when combined with sodium chloride and DNase I. In combination with DNase I, D-BMAP18 discouraged the deposition of new biofilm and eradicated preformed biofilms of some P. aeruginosa strains. In addition, D-BMAP18 down regulated the production of TNF-α, IL1-β, and TGF-β in LPS-stimulated or IFN-γ macrophages derived from THP-1 cells indicating an anti-inflammatory activity. The biocompatibility of D-BMAP18 was assessed using four different cell lines, showing that residual cell-specific cytotoxicity at bactericidal concentrations could be abolished by the presence of CF sputum. Overall, this study suggests that D-BMAP18 may be an interesting molecule as a starting point to develop a novel therapeutic agent to simultaneously contrast lung infections and inflammation in CF patients.

scholarly journals In Vitro Activity of Ceftolozane-Tazobactam and Other Antimicrobial Agents against Burkholderia cepacia Complex and Burkholderia gladioli

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
Dale M. Mazer ◽  
Carol Young ◽  
Linda M. Kalikin ◽  
Theodore Spilker ◽  
John J. LiPuma
Keyword(s):  
Cystic Fibrosis ◽  
Burkholderia Cepacia ◽  
Antimicrobial Agents ◽  
Vitro Activity ◽  
Burkholderia Cepacia Complex ◽  
In Vitro Activity ◽  
Content Type ◽  
Burkholderia Gladioli

ABSTRACT We tested the activities of ceftolozane-tazobactam and 13 other antimicrobial agents against 221 strains of Burkholderia cepacia complex and Burkholderia gladioli. Most strains (82%) were cultured from persons with cystic fibrosis, and most (85%) were recovered since 2011. The ceftolozane-tazobactam MIC was ≤8 μg/ml for 77% of the strains. However, the MIC range was broad (≤0.5 to >64 μg/ml; MIC50/90, 2/32 μg/ml). Significant differences in susceptibility to some antimicrobial agents were observed between species.

scholarly journals Blocking the alternative sigma factor RpoN reduces virulence ofPseudomonas aeruginosaisolated from cystic fibrosis patients and increases antibiotic sensitivity in a laboratory strain

2018 ◽  
Author(s):  
MG Lloyd ◽  
JL Vossler ◽  
CT Nomura ◽  
JF Moffat
Keyword(s):  
Cystic Fibrosis ◽  
Sigma Factor ◽  
Antimicrobial Agents ◽  
Laboratory Strain ◽  
Infection Model ◽  
Alternative Sigma Factor ◽  
Beta Lactam ◽  
Cis Acting

AbstractMultidrug-resistant organisms (MDROs) are increasing in the health care setting, and there are few antimicrobial agents available to treat infections caused by these bacteria.Pseudomonas aeruginosais an opportunistic pathogen in burn patients and individuals with cystic fibrosis (CF), and a leading cause of nosocomial infections.P. aeruginosais inherently resistant to many antibiotics and can develop or acquire resistance to others, limiting options for treatment.P. aeruginosahas virulence factors that are regulated by sigma factors in response to the tissue microenvironment. The alternative sigma factor, RpoN (σ54), regulates many virulence genes and is linked to antibiotic resistance. Recently, we described a cis-acting peptide, RpoN*, which acts as a “molecular roadblock”, binding RpoN consensus promoters at the −24 site and blocking transcription. RpoN* reduces virulence ofP. aeruginosalaboratory strains bothin vitroandin vivo,but its effects in clinical isolates was not known. We investigated the effects of RpoN* on phenotypically variedP. aeruginosastrains isolated from cystic fibrosis patients. RpoN* expression reduced motility, biofilm formation, and pathogenesis in aP. aeruginosa – C. elegansinfection model. RpoN* expression increased susceptibility to several beta-lactam based antibiotics in the lab strainP. aeruginosaPA19660Xen5. Here, we show that using a cis-acting peptide to block RpoN consensus promoters has potential clinical implications in reducing virulence and enhancing the activity of antibiotics.

scholarly journals In Vitro Activity of 22 Antibiotics against Achromobacter Isolates from People with Cystic Fibrosis. Are There New Therapeutic Options?

2021 ◽  
Vol 9 (12) ◽  
pp. 2473
Author(s):  
Clémence Beauruelle ◽  
Claudie Lamoureux ◽  
Arsid Mashi ◽  
Sophie Ramel ◽  
Jean Le Bihan ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Antibiotic Susceptibility ◽  
Antimicrobial Agents ◽  
Multidrug Resistant ◽  
Therapeutic Options ◽  
In Vitro Activity ◽  
Therapeutic Guidelines ◽  
First Results ◽  
New Antibiotics

Bacteria belonging to the genus Achromobacter are increasingly isolated from respiratory samples of people with cystic fibrosis (PWCF). The management of this multidrug-resistant genus is challenging and characterised by a lack of international recommendations, therapeutic guidelines and data concerning antibiotic susceptibility, especially concerning the newer antibiotics. The objective of this study was to describe the antibiotic susceptibility of Achromobacter isolates from PWCF, including susceptibility to new antibiotics. The minimum inhibitory concentrations (MICs) of 22 antibiotics were determined for a panel of 23 Achromobacter isolates from 19 respiratory samples of PWCF. Two microdilution MIC plates were used: EUMDROXF® plate (Sensititre) and Micronaut-S Pseudomonas MIC® plate (Merlin) and completed by a third method if necessary (E-test® or UMIC®). Among usual antimicrobial agents, the most active was imipenem (70% susceptibility). Trimethoprim-sulfamethoxazole, piperacillin and tigecycline (65%, 56% and 52% susceptibility, respectively) were still useful for the treatment of Achromobacter infections. Among new therapeutic options, β-lactams combined with a β-lactamase-inhibitor did not bring benefits compared to β-lactam alone. On the other hand, cefiderocol appeared as a promising therapeutic alternative for managing Achromobacter infections in PWCF. This study provides the first results on the susceptibility of clinical Achromobacter isolates concerning new antibiotics. More microbiological and clinical data are required to establish the optimal treatment of Achromobacter infections.

scholarly journals DivergentIn vitroMIC Characteristics and underlying isogenic mutations in host-specializedPseudomonas aeruginosa

2017 ◽  
Author(s):  
Xuan Qin ◽  
Alexander L Greninger ◽  
Chuan Zhou ◽  
Amanda Adler ◽  
Shuhua Yuan ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Antimicrobial Agents ◽  
Drug Susceptibility ◽  
Resistance Rate ◽  
Loss Of Function ◽  
Cellular Functions ◽  
Dna Mismatch ◽  
Compare And Contrast

AbstractClinical isolates ofPseudomonas aeruginosa (Pa)from patients with cystic fibrosis (CF) are known to differ from those associated with infections of non-CF hosts in colony morphology, drug susceptibility patterns, and genomic hypermutability. AlthoughPaisolates from CF have long been recognized for their overall higher resistance rate calculated generally by reduced “percent susceptible”, this study takes the approach to compare and contrast Etest MIC distributions between two distinct cohorts of clinical strains (n=224 from 56 CF patients and n=130 from 68 non-CF patients respectively) isolated in 2013. Logarithmic transformed MIC (logMIC) values of 11 antimicrobial agents were compared between the two groups. CF isolates tended to produce heterogeneous and widely dispersed MICs compared to non-CF isolates. By applying a test for equality of variances, we were able to confirm that the MICs generated from CF isolates against 9 out of the 11 agents were significantly more dispersed than those from non-CF (p<0.02-<0.001). Quantile-quantiles plots indicated little agreement between the two cohorts of isolates. Based on whole genome sequencing of 19 representative CFPaisolates, divergent gain- or loss-of-function mutations in efflux and porin genes and their regulators between isogenic or intra-clonal associates were evident. Not one, not a few, but the net effect all adaptive mutational changes in the genomes of CFPa, both shared and unshared between isogenic strains, are responsible for the divergent heteroresistance patterns. Moreover, the isogenic variations are suggestive of a bacterial syntrophic lifestyle when “lockedȍ inside a host focal airway environment over prolonged periods.Significance statementBacterial heteroresistance is associated with niche specialized organisms interacting with host species for prolonged period of time, medically characterized by “chronic focal infections”. A prime example is found inPseudomonas aeruginosaisogenic/non-homogeneous isolates from patient airways with cystic fibrosis. The development of pseudomonal polarizing MICsin vitroto many actively used antimicrobial agents among isogenic isolates and “Eagle-type” heteroresistance patterns are common and characteristic. Widespread isogenic gene lesions were evident for defects in drug transporters, DNA mismatch repair, and many other structural or cellular functions—a result of pseudomonal symbiotic response to host selection. Co-isolation of extremely susceptible and resistant isogenicPastrains suggests intra-airway evolution of a multicellular syntrophic bacterial lifestyle, which has laboratory interpretation and clinical treatment implications.

Sign in / Sign up

Export Citation Format

Share Document