scholarly journals Chemical Synergy between Ionophore PBT2 and Zinc Reverses Antibiotic Resistance

mBio ◽  
2018 ◽  
Vol 9 (6) ◽  
Author(s):  
Lisa Bohlmann ◽  
David M. P. De Oliveira ◽  
Ibrahim M. El-Deeb ◽  
Erin B. Brazel ◽  
Nichaela Harbison-Price ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibiotic Resistance ◽  
Global Health ◽  
Antibiotic Treatment ◽  
Acquired Resistance ◽  
Gram Positive ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Antibiotic Development ◽  
Vancomycin Resistant

ABSTRACT The World Health Organization reports that antibiotic-resistant pathogens represent an imminent global health disaster for the 21st century. Gram-positive superbugs threaten to breach last-line antibiotic treatment, and the pharmaceutical industry antibiotic development pipeline is waning. Here we report the synergy between ionophore-induced physiological stress in Gram-positive bacteria and antibiotic treatment. PBT2 is a safe-for-human-use zinc ionophore that has progressed to phase 2 clinical trials for Alzheimer’s and Huntington’s disease treatment. In combination with zinc, PBT2 exhibits antibacterial activity and disrupts cellular homeostasis in erythromycin-resistant group A Streptococcus (GAS), methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE). We were unable to select for mutants resistant to PBT2-zinc treatment. While ineffective alone against resistant bacteria, several clinically relevant antibiotics act synergistically with PBT2-zinc to enhance killing of these Gram-positive pathogens. These data represent a new paradigm whereby disruption of bacterial metal homeostasis reverses antibiotic-resistant phenotypes in a number of priority human bacterial pathogens. IMPORTANCE The rise of bacterial antibiotic resistance coupled with a reduction in new antibiotic development has placed significant burdens on global health care. Resistant bacterial pathogens such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus are leading causes of community- and hospital-acquired infection and present a significant clinical challenge. These pathogens have acquired resistance to broad classes of antimicrobials. Furthermore, Streptococcus pyogenes, a significant disease agent among Indigenous Australians, has now acquired resistance to several antibiotic classes. With a rise in antibiotic resistance and reduction in new antibiotic discovery, it is imperative to investigate alternative therapeutic regimens that complement the use of current antibiotic treatment strategies. As stated by the WHO Director-General, “On current trends, common diseases may become untreatable. Doctors facing patients will have to say, Sorry, there is nothing I can do for you.”

scholarly journals Activities of Oxadiazole Antibacterials against Staphylococcus aureus and Other Gram-Positive Bacteria

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Sara Ceballos ◽  
Choon Kim ◽  
Derong Ding ◽  
Shahriar Mobashery ◽  
Mayland Chang ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Gram Positive ◽  
Methicillin Resistant ◽  
Content Type ◽  
Gram Positive Bacteria ◽  
Vancomycin Resistant Enterococci ◽  
Vancomycin Resistant ◽  
Mrsa Strains

ABSTRACT The activities of four oxadiazoles were investigated with 210 methicillin-resistant Staphylococcus aureus (MRSA) strains. MIC50 and MIC90 values of 1 to 2 and 4 μg/ml, respectively, were observed. We also evaluated the activity of oxadiazole ND-421 against other staphylococci and enterococci and in the presence of oxacillin for selected MRSA strains. The MIC for ND-421 is lowered severalfold in combination with oxacillin, as they synergize. The MIC90 of ND-421 against vancomycin-resistant enterococci is ≤1 μg/ml.

scholarly journals New Gram-Positive Agents: the Next Generation of Oxazolidinones and Lipoglycopeptides

2016 ◽  
Vol 54 (9) ◽  
pp. 2225-2232 ◽  
Author(s):  
Matthew P. Crotty ◽  
Tamara Krekel ◽  
Carey-Ann D. Burnham ◽  
David J. Ritchie
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Resistance ◽  
Next Generation ◽  
Gram Positive ◽  
Content Type ◽  
Skin Structure ◽  
Vancomycin Resistant Enterococci ◽  
Vancomycin Resistant ◽  
The U.S

The growing problem of antimicrobial resistance among bacterial pathogens, including methicillin-resistantStaphylococcus aureus(MRSA) and vancomycin-resistant enterococci (VRE), has reached a critical state. Tedizolid phosphate, dalbavancin, and oritavancin have recently been approved by the U.S. Food and Drug Administration (FDA) for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and represent the next generation of oxazolidinones and lipoglycopeptides. All three agents exhibitin vitroactivity and clinical efficacy against MRSA. Tedizolid phosphate and oritavancin demonstratein vitroactivity against VRE. These new Gram-positive agents are reviewed here.

scholarly journals In VivoAntibacterial Activity of MRX-I, a New Oxazolidinone

2014 ◽  
Vol 58 (4) ◽  
pp. 2418-2421 ◽  
Author(s):  
Cong-Ran Li ◽  
Qian-Qian Zhai ◽  
Xiu-Kun Wang ◽  
Xin-Xin Hu ◽  
Guo-Qing Li ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Streptococcus Pneumoniae ◽  
Local Infection ◽  
Gram Positive ◽  
Methicillin Resistant ◽  
Content Type ◽  
Vancomycin Resistant Enterococci ◽  
Infection Models ◽  
Vancomycin Resistant

ABSTRACTMRX-I is a potent oxazolidinone antibiotic against Gram-positive pathogens, including methicillin-resistantStaphylococcus aureus(MRSA), penicillin-resistantStreptococcus pneumoniae(PRSP), penicillin-intermediateS. pneumoniae(PISP), and vancomycin-resistant enterococci (VRE). In this study, thein vivoefficacy of orally administered MRX-I was evaluated using linezolid as a comparator. MRX-I showed the same or better efficacy than linezolid in both systemic and local infection models against the tested strains.

scholarly journals IncM Plasmid R1215 Is the Source of Chromosomally Located Regions Containing Multiple Antibiotic Resistance Genes in the Globally Disseminated Acinetobacter baumannii GC1 and GC2 Clones

mSphere ◽  
2016 ◽  
Vol 1 (3) ◽  
Author(s):  
Grace A. Blackwell ◽  
Mohammad Hamidian ◽  
Ruth M. Hall
Keyword(s):  
Antibiotic Resistance ◽  
Resistance Genes ◽  
Acquired Resistance ◽  
Antibiotic Resistance Genes ◽  
Modern Medicine ◽  
Single Step ◽  
Multiple Antibiotic Resistance ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Resistance Island

ABSTRACT Two lineages of extensively antibiotic-resistant A. baumannii currently plaguing modern medicine each acquired resistance to all of the original antibiotics (ampicillin, tetracycline, kanamycin, and sulfonamides) by the end of the 1970s and then became resistant to antibiotics from newer families after they were introduced in the 1980s. Here, we show that, in both of the dominant globally disseminated A. baumannii clones, a related set of antibiotic resistance genes was acquired together from the same resistance region that had already evolved in an IncM plasmid. In both cases, the action of IS26 was important in this process, but homologous recombination was also involved. The findings highlight the fact that complex regions carrying several resistance genes can evolve in one location or organism and all or part of the evolved region can then move to other locations and other organisms, conferring resistance to several antibiotics in a single step. Clear similarities between antibiotic resistance islands in the chromosomes of extensively antibiotic-resistant isolates from the two dominant, globally distributed Acinetobacter baumannii clones, GC1 and GC2, suggest a common origin. A close relative of the likely progenitor of both of these regions was found in R1215, a conjugative IncM plasmid from a Serratia marcescens strain isolated prior to 1980. The 37.8-kb resistance region in R1215 lies within the mucB gene and includes aacC1, aadA1, aphA1b, bla TEM, catA1, sul1, and tetA(A), genes that confer resistance to gentamicin, streptomycin and spectinomycin, kanamycin and neomycin, ampicillin, chloramphenicol, sulfamethoxazole, and tetracycline, respectively. The backbone of this region is derived from Tn1721 and is interrupted by a hybrid Tn2670 (Tn21)-Tn1696-type transposon, Tn6020, and an incomplete Tn1. After minor rearrangements, this R1215 resistance island can generate AbGRI2-0*, the predicted earliest form of the IS26-bounded AbGRI2-type resistance island of GC2 isolates, and to the multiple antibiotic resistance region (MARR) of AbaR0, the precursor of this region in AbaR-type resistance islands in the GC1 group. A 29.9-kb circle excised by IS26 has been inserted into the A. baumannii chromosome to generate AbGRI2-0*. To create the MARR of AbaR0, a different circular form, again generated by IS26 from an R1215 resistance region variant, has been opened at a different point by recombination with a copy of the sul1 gene already present in the AbaR precursor. Recent IncM plasmids related to R1215 have a variant resistance island containing a bla SHV gene in the same location. IMPORTANCE Two lineages of extensively antibiotic-resistant A. baumannii currently plaguing modern medicine each acquired resistance to all of the original antibiotics (ampicillin, tetracycline, kanamycin, and sulfonamides) by the end of the 1970s and then became resistant to antibiotics from newer families after they were introduced in the 1980s. Here, we show that, in both of the dominant globally disseminated A. baumannii clones, a related set of antibiotic resistance genes was acquired together from the same resistance region that had already evolved in an IncM plasmid. In both cases, the action of IS26 was important in this process, but homologous recombination was also involved. The findings highlight the fact that complex regions carrying several resistance genes can evolve in one location or organism and all or part of the evolved region can then move to other locations and other organisms, conferring resistance to several antibiotics in a single step.

scholarly journals Activity of a Novel Cyclic Lipopeptide, CB-183,315, against Resistant Clostridium difficile and Other Gram-Positive Aerobic and Anaerobic Intestinal Pathogens

2012 ◽  
Vol 56 (6) ◽  
pp. 3448-3452 ◽  
Author(s):  
D. R. Snydman ◽  
N. V. Jacobus ◽  
L. A. McDermott
Keyword(s):  
Staphylococcus Aureus ◽  
Clostridium Difficile ◽  
Vancomycin Resistant Enterococcus ◽  
Gram Positive ◽  
Content Type ◽  
Cyclic Lipopeptide ◽  
Excellent Activity ◽  
Intestinal Pathogens ◽  
Vancomycin Resistant ◽  
Aerobic And Anaerobic

ABSTRACTWe evaluated the activity of CB-183,315 againstClostridium difficile, including strains that are resistant to fluoroquinolones and metronidazole and with elevated MICs to vancomycin as well as other Gram-positive intestinal pathogens. The MICs of CB-183,315 against allC. difficileisolates were ≤1 μg/ml. CB-183,315 had greater activity than vancomycin and metronidazole againstC. difficileisolates and was more active than the comparators against vancomycin-resistant enterococcus (VRE). CB-183,315 also had excellent activity against methicillin-resistantStaphylococcus aureus(MRSA), otherClostridiumspp., andPeptostreptococcusspp.

scholarly journals Antimicrobial Activity of Omadacycline Tested against Clinical Bacterial Isolates from Hospitals in Mainland China, Hong Kong, and Taiwan: Results from the SENTRY Antimicrobial Surveillance Program (2013 to 2016)

2019 ◽  
Vol 63 (3) ◽  
Author(s):  
Cecilia G. Carvalhaes ◽  
Michael D. Huband ◽  
Harald H. Reinhart ◽  
Robert K. Flamm ◽  
Helio S. Sader
Keyword(s):  
Staphylococcus Aureus ◽  
Hong Kong ◽  
Klebsiella Oxytoca ◽  
Surveillance Program ◽  
Gram Positive ◽  
Gram Negative ◽  
Content Type ◽  
Vancomycin Resistant ◽  
Geographic Regions

ABSTRACTOmadacycline is a derivative of minocycline and the first agent of the aminomethylcycline class. A total of 3,282 organisms (1 per patient) were consecutively collected from patients hospitalized in China (including Hong Kong) and Taiwan. Susceptibility testing was performed by broth microdilution methods in a central laboratory (JMI Laboratories). The collection included Gram-positive and Gram-negative organisms from patients with pneumonia, bloodstream, skin, community-acquired respiratory, and other infections. Omadacycline was very potent againstStaphylococcus aureus(n= 689; MIC50/90, 0.12/0.25 mg/liter), including methicillin-resistantStaphylococcus aureus(MRSA;n= 299; MIC50/90, 0.12/0.5 mg/liter), and had similar activity across geographic regions. Omadacycline was very active againstStreptococcus pneumoniae(highest MIC, 0.25 mg/liter), β-hemolytic streptococci (highest MIC, 1 mg/liter), viridans group streptococci (highest MIC, 0.25 mg/liter), andEnterococcusspp. (highest MIC, 0.5 mg/liter) from all geographic regions. Overall, 53.8% ofS. pneumoniaeisolates were penicillin resistant (penicillin MIC, ≥2 mg/liter) and 10.7% of enterococci (21.2% amongE. faeciumisolates) were vancomycin resistant. Omadacycline was active againstHaemophilus influenzae(MIC50/90, 0.5/1 mg/liter) regardless of β-lactamase production and was active againstMoraxella catarrhalis(MIC50/90, ≤0.12/0.25 mg/liter). AgainstEnterobacteriaceae, omadacycline was most active againstEscherichia coli(MIC50/90, 1/2 mg/liter),Klebsiella oxytoca(MIC50/90, 1/4 mg/liter), andEnterobacter cloacae(MIC50/90, 2/4 mg/liter). Omadacycline had potentin vitroactivity against Gram-positive and Gram-negative pathogens isolated from China and Taiwan and retained activity against problem pathogens, such as MRSA, vancomycin-resistant enterococci (VRE), penicillin-resistantS. pneumoniae(PRSPN), and extended-spectrum β-lactamase-producingE. coli. The observed MIC profile in Chinese isolates was very similar to that seen in the U.S. and European surveillance studies.

scholarly journals In Vitro and In Vivo Activities of DA-7867, a New Oxazolidinone, against Aerobic Gram-Positive Bacteria

2005 ◽  
Vol 49 (6) ◽  
pp. 2498-2500 ◽  
Author(s):  
Eun Jeong Yoon ◽  
Yeong Woo Jo ◽  
Sung Hak Choi ◽  
Tae Ho Lee ◽  
Jae Keol Rhee ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Streptococcus Pneumoniae ◽  
Gram Positive ◽  
Methicillin Resistant ◽  
Gram Positive Bacteria ◽  
Vancomycin Resistant Enterococci ◽  
Infection Models ◽  
Vancomycin Resistant

ABSTRACT In vitro and in vivo activities of DA-7867 were assessed against methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and penicillin-resistant Streptococcus pneumoniae. All isolates were inhibited by DA-7867 at ≤0.78 μg/ml, a four-times-lower concentration than that of inhibition by linezolid. For murine infection models, DA-7867 also exhibited greater efficacy than linezolid against all isolates tested.

scholarly journals Evidence of Another Anthropic Impact on Iguana delicatissima from the Lesser Antilles: The Presence of Antibiotic Resistant Enterobacteria

Antibiotics ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 885
Author(s):  
Gustavo Di Lallo ◽  
Marco Maria D’Andrea ◽  
Samanta Sennati ◽  
Maria Cristina Thaller ◽  
Luciana Migliore ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Animal Species ◽  
Susceptibility Testing ◽  
Acquired Resistance ◽  
Climatic Conditions ◽  
Antibiotic Resistant ◽  
Associated Bacteria ◽  
Improper Use ◽  
Resistant Strains ◽  
Drug Resistant Strains

The improper use of antibiotics by humans may promote the dissemination of resistance in wildlife. The persistence and spread of acquired antibiotic resistance and human-associated bacteria in the environment, while representing a threat to wildlife, can also be exploited as a tool to monitor the extent of human impact, particularly on endangered animal species. Hence, we investigated both the associated enterobacterial species and the presence of acquired resistance traits in the cloacal microbiota of the critically endangered lesser Antillean iguana (Iguana delicatissima), by comparing two separate populations living in similar climatic conditions but exposed to different anthropic pressures. A combination of techniques, including direct plating, DNA sequencing and antimicrobial susceptibility testing allowed us to characterize the dominant enterobacterial populations, the antibiotic resistant strains and their profiles. A higher frequency of Escherichia coli was found in the samples from the more anthropized site, where multi-drug resistant strains were also isolated. These results confirm how human-associated bacteria as well as their antibiotic-resistance determinants may be transferred to wildlife, which, in turn, may act as a reservoir of antibiotic resistance.

Activity of Oritavancin Against Gram-positive Pathogens Causing Bloodstream Infections in the United States Over 10 Years: Focus on Drug-Resistant Enterococcal Subsets (2010-2019)

2021 ◽  
Author(s):  
Cecilia G. Carvalhaes ◽  
Helio S. Sader ◽  
Jennifer M. Streit ◽  
Mariana Castanheira ◽  
Rodrigo E. Mendes
Keyword(s):  
United States ◽  
Staphylococcus Aureus ◽  
Enterococcus Faecium ◽  
Bloodstream Infections ◽  
The United States ◽  
Drug Resistant ◽  
Gram Positive ◽  
Methicillin Resistant ◽  
Vancomycin Resistant ◽  
Over Time

Oritavancin displayed potent and stable activity (MIC 90 range, 0.06-0.5 mg/L) over time (2010-2019) against Gram-positive pathogens causing bloodstream infections, including methicillin-resistant Staphylococcus aureus and resistant subsets of Enterococcus spp. Daptomycin and linezolid were also active against methicillin-resistant S. aureus and vancomycin-resistant Enterococcus . Only oritavancin and linezolid remained active against Enterococcus faecium isolates displaying an elevated daptomycin MIC (i.e., 2-4 mg/L). Proportions of methicillin-resistant S. aureus and vancomycin-resistant Enterococcus within the respective S. aureus and enterococcal populations decreased over this period.

scholarly journals Quantifying the Exposure to Antibiotic-Resistant Pathogens Among Patients Discharged From a Single Hospital Across All California Healthcare Facilities

2015 ◽  
Vol 36 (11) ◽  
pp. 1275-1282 ◽  
Author(s):  
Rupak Datta ◽  
Shawn Brown ◽  
Vinh Q. Nguyen ◽  
Chenghua Cao ◽  
John Billimek ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Nursing Homes ◽  
Hospital Readmissions ◽  
Time Dependent ◽  
Antibiotic Resistant ◽  
Total Exposure ◽  
Healthcare Facilities ◽  
Vancomycin Resistant Enterococci ◽  
Vancomycin Resistant

OBJECTIVETo assess the time-dependent exposure of California healthcare facilities to patients harboring methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), extended-spectrum β-lactamase (ESBL)–producing Escherichia coli and Klebsiella pneumoniae, and Clostridium difficile infection (CDI) upon discharge from 1 hospital.METHODSRetrospective multiple-cohort study of adults discharged from 1 hospital in 2005–2009, counting hospitals, nursing homes, cities, and counties in which carriers were readmitted, and comparing the number and length of stay of readmissions and the number of distinct readmission facilities among carriers versus noncarriers.RESULTSWe evaluated 45,772 inpatients including those with MRSA (N=1,198), VRE (N=547), ESBL (N=121), and CDI (N=300). Within 1 year of discharge, MRSA, VRE, and ESBL carriers exposed 137, 117, and 45 hospitals and 103, 83, and 37 nursing homes, generating 58,804, 33,486, and 15,508 total exposure-days, respectively. Within 90 days of discharge, CDI patients exposed 36 hospitals and 35 nursing homes, generating 7,318 total exposure-days. Compared with noncarriers, carriers had more readmissions to hospitals (MRSA:1.8 vs 0.9/patient; VRE: 2.6 vs 0.9; ESBL: 2.3 vs 0.9; CDI: 0.8 vs 0.4; all P<.001) and nursing homes (MRSA: 0.4 vs 0.1/patient; VRE: 0.7 vs 0.1; ESBL: 0.7 vs 0.1; CDI: 0.3 vs 0.1; all P<.001) and longer hospital readmissions (MRSA: 8.9 vs 7.3 days; VRE: 8.9 vs 7.4; ESBL: 9.6 vs 7.5; CDI: 12.3 vs 8.2; all P<.01).CONCLUSIONSPatients harboring antibiotic-resistant pathogens rapidly expose numerous facilities during readmissions; regional containment strategies are needed.Infect. Control Hosp. Epidemiol. 2015;36(11):1275–1282

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