- Award ID(s):
- 1854934
- NSF-PAR ID:
- 10352282
- Author(s) / Creator(s):
- ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; more »
- Date Published:
- Journal Name:
- Clinical infectious diseases
- Volume:
- 73
- ISSN:
- 1058-4838
- Page Range / eLocation ID:
- e39
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
null (Ed.)Abstract Background Acinetobacter baumannii is a gram-negative bacterium which causes opportunistic infections in immunocompromised hosts. Genome plasticity has given rise to a wide range of strain variation with respect to antimicrobial resistance profiles and expression of virulence factors which lead to altered phenotypes associated with pathogenesis. The purpose of this study was to analyze clinical strains of A. baumannii for phenotypic variation that might correlate with virulence phenotypes, antimicrobial resistance patterns, or strain isolation source. We hypothesized that individual strain virulence phenotypes might be associated with anatomical site of isolation or alterations in susceptibility to antimicrobial interventions. Methodology A cohort of 17 clinical isolates of A. baumannii isolated from diverse anatomical sites were evaluated to ascertain phenotypic patterns including biofilm formation, hemolysis, motility, and antimicrobial resistance. Antibiotic susceptibility/resistance to ampicillin-sulbactam, amikacin, ceftriaxone, ceftazidime, cefotaxime, ciprofloxacin, cefepime, gentamicin, levofloxacin, meropenem, piperacillin, trimethoprim-sulfamethoxazole, ticarcillin- K clavulanate, tetracyclin, and tobramycin was determined. Results Antibiotic resistance was prevalent in many strains including resistance to ampicillin-sulbactam, amikacin, ceftriaxone, ceftazidime, cefotaxime, ciprofloxacin, cefepime, gentamicin, levofloxacin, meropenem, piperacillin, trimethoprim-sulfamethoxazole, ticarcillin- K clavulanate, tetracyclin, and tobramycin. All strains tested induced hemolysis on agar plate detection assays. Wound-isolated strains of A. baumannii exhibited higher motility than strains isolated from blood, urine or Foley catheter, or sputum/bronchial wash. A. baumannii strains isolated from patient blood samples formed significantly more biofilm than isolates from wounds, sputum or bronchial wash samples. An inverse relationship between motility and biofilm formation was observed in the cohort of 17 clinical isolates of A. baumannii tested in this study. Motility was also inversely correlated with induction of hemolysis. An inverse correlation was observed between hemolysis and resistance to ticarcillin-k clavulanate, meropenem, and piperacillin. An inverse correlation was also observed between motility and resistance to ampicillin-sulbactam, ceftriaxone, ceftoxamine, ceftazidime, ciprofloxacin, or levofloxacin. Conclusions Strain dependent variations in biofilm and motility are associated with anatomical site of isolation. Biofilm and hemolysis production both have an inverse association with motility in the cohort of strains utilized in this study, and motility and hemolysis were inversely correlated with resistance to numerous antibiotics.more » « less
-
Abstract Rapid identification of antibiotic-resistant bacteria will play a key role in solving the global antibiotic crisis by providing a route to targeted antibiotic administration. However, current bacterial infection diagnoses take up to 3 days which can lead to antibiotic treatment that is less effective. Here we report a microfluidic system with a ladder shaped design allowing us to generate a twofold serial dilution of antibiotics comparable to current national and international standards. Our consolidated design, with minimal handling steps cuts down the testing time for antibiotic susceptibility from 16–20 h to 4–5 h. Our feasibility testing results are consistent with the commercial antibiotic susceptibility testing (AST) results, showing a 91.75% rate of agreement for Gram-negative and Gram-positive bacterial isolated from canine urinary tract infections (UTI) and may be used without prior isolation or enrichment. This platform provides an adaptable and efficient diagnostic tool for antibiotic susceptibility testing.
-
Abstract Background Antimicrobial resistance (AMR) is a global health concern. High-throughput metagenomic sequencing of microbial samples enables profiling of AMR genes through comparison with curated AMR databases. However, the performance of current methods is often hampered by database incompleteness and the presence of homology/homoplasy with other non-AMR genes in sequenced samples.
Results We present AMR-meta, a database-free and alignment-free approach, based on k-mers, which combines algebraic matrix factorization into metafeatures with regularized regression. Metafeatures capture multi-level gene diversity across the main antibiotic classes. AMR-meta takes in reads from metagenomic shotgun sequencing and outputs predictions about whether those reads contribute to resistance against specific classes of antibiotics. In addition, AMR-meta uses an augmented training strategy that joins an AMR gene database with non-AMR genes (used as negative examples). We compare AMR-meta with AMRPlusPlus, DeepARG, and Meta-MARC, further testing their ensemble via a voting system. In cross-validation, AMR-meta has a median f-score of 0.7 (interquartile range, 0.2–0.9). On semi-synthetic metagenomic data—external test—on average AMR-meta yields a 1.3-fold hit rate increase over existing methods. In terms of run-time, AMR-meta is 3 times faster than DeepARG, 30 times faster than Meta-MARC, and as fast as AMRPlusPlus. Finally, we note that differences in AMR ontologies and observed variance of all tools in classification outputs call for further development on standardization of benchmarking data and protocols.
Conclusions AMR-meta is a fast, accurate classifier that exploits non-AMR negative sets to improve sensitivity and specificity. The differences in AMR ontologies and the high variance of all tools in classification outputs call for the deployment of standard benchmarking data and protocols, to fairly compare AMR prediction tools.
-
Abstract Each year, thousands of patients die from antimicrobial‐resistant bacterial infections that fail to respond to conventional antibiotic treatment. Antimicrobial polymers are a promising new method of combating antibiotic‐resistant bacterial infections. We have previously reported the synthesis of a series of narrow‐spectrum peptidomimetic antimicrobial polyurethanes that are effective against Gram‐negative bacteria, such as
; however, these polymers are not effective against Gram‐positive bacteria, such asEscherichia coli . With the aim of understanding the correlation between chemical structure and antibacterial activity, we have subsequently developed three structural variants of these antimicrobial polyurethanes using post‐polymerization modification with decanoic acid and oleic acid. Our results show that such modifications converted the narrow‐spectrum antibacterial activity of these polymers into broad‐spectrum activity against Gram‐positive species such asStaphylococcus aureus , however, also increasing their toxicity to mammalian cells. Mechanistic studies of bacterial membrane disruption illustrate the differences in antibacterial action between the various polymers. The results demonstrate the challenge of balancing antimicrobial activity and mammalian cell compatibility in the design of antimicrobial polymer compositions. © 2019 Society of Chemical IndustryS. aureus -
Abstract Antimicrobial drug resistance demands novel approaches for improving the efficacy of antibiotics, especially against Gram‐negative bacteria. Herein, we report that conjugating a diglycine (GG) to an antibiotic prodrug drastically accelerates intrabacterial ester‐bond hydrolysis required for activating the antibiotic. Specifically, the attachment of GG to chloramphenicol succinate (CLsu) generates CLsuGG, which exhibits about an order of magnitude higher inhibitory efficacy than CLsu against
Escherichia coli . Further studies reveal that CLsuGG undergoes rapid hydrolysis, catalyzed by intrabacterial esterases (e.g., BioH and YjfP), to generate chloramphenicol (CL) inE. coli . Importantly, the conjugate exhibits lower cytotoxicity to bone marrow stromal cells than CL. Structural analogues of CLsuGG indicate that the conjugation of GG to an antibiotic prodrug is an effective strategy for accelerating enzymatic prodrug hydrolysis and enhancing the antibacterial efficacy of antibiotics.