Tom Parr

Indiana University, Biology, Department Member

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Papers by Tom Parr

Lipopolysaccharide-free Escherichia coli OmpF and Pseudomonas aeruginosa protein P porins are functionally active in lipid bilayer membranes

Journal of Bacteriology, Feb 1, 1986

Escherichia coli porin OmpF and Pseudomonas aeruginosa porin protein P were eluted from sodium do... more Escherichia coli porin OmpF and Pseudomonas aeruginosa porin protein P were eluted from sodium dodecyl sulfate-polyacrylamide gels. The resultant porin preparations were found to be devoid of detectable lipopolysaccharide (LPS) by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and silver staining for LPS, direct enzyme-linked immunosorbent assays with LPS-specific monoclonal antibodies, and 2-keto-3deoxyoctulosonic acid assays. The average conductances, ionic selectivities and incorporation rates of the electroeluted porins were identical to those of their conventionally purified counterparts. These data suggest that LPS is not required per se for porin function.

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Modes of action and inhibitory activities of new siderophore-beta-lactam conjugates that use specific iron uptake pathways for entry into bacteria

Antimicrobial Agents and Chemotherapy, 1992

We describe here the mechanism of inhibition of two new siderophore-beta-lactam conjugates agains... more We describe here the mechanism of inhibition of two new siderophore-beta-lactam conjugates against Escherichia coli X580. One conjugate is a spermidine-based catechol siderophore-carbacephalosporin (JAM-2-263), and the other is an N5-acetyl-N5-hydroxy-L-ornithine tripeptide hydroxamate siderophore-carbacephalosporin (EKD-3-88). In an agar diffusion test, both conjugates produced large inhibitory zones against strain X580. Resistant strains (i.e., JAMR and EKDR) could be isolated after exposure of X580 to the conjugates JAM-2-263 and EKD-3-88, respectively. No cross-resistance was observed in these individual isolates. JAMR and EKDR were studied further to elucidate the mechanism of inhibition of each conjugated drug. The affinities of JAM-2-263 and EKD-3-88 for penicillin-binding proteins (PBPs) of isolated inner membranes were determined by a competition assay with 125I-penicillin V. JAM-2-263 targeted primarily PBPs 1A/B and 5/6, while EKD-3-88 targeted PBPs 1A/B and 3. Strains X5...

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Running title: Oritavancin is active against S. aureus in tolerant states 2

Slow-growing bacteria and biofilms are notoriously tolerant to antibiotics. Oritavancin is a lipo... more Slow-growing bacteria and biofilms are notoriously tolerant to antibiotics. Oritavancin is a lipoglycopeptide with multiple mechanisms of action that contribute to its bactericidal action against exponentially growing gram-positive pathogens, including the inhibition of cell wall synthesis and perturbation of membrane barrier function. We sought to determine whether oritavancin could eradicate cells known to be tolerant to many antimicrobial agents, that is, stationary-phase and biofilm cultures of Staphylococcus aureus in vitro. Oritavancin exhibited concentration-dependent bactericidal activity against stationaryphase inocula of methicillin-susceptible S. aureus (MSSA) ATCC 29213, methicillin-resistant S. aureus (MRSA) ATCC 33591, and vancomycin-resistant S. aureus (VRSA) VRS5 inoculated into nutrient-depleted cation-adjusted Mueller-Hinton broth. As has been described for exponential-phase cells, oritavancin induced membrane depolarization, increased membrane permeability, and caused ultrastructural defects including a loss of nascent septal cross walls in stationary-phase MSSA. Furthermore, oritavancin sterilized biofilms of MSSA, MRSA, and VRSA at minimal biofilm eradication concentrations (MBECs) of between 0.5 and 8 g/ml. Importantly, MBECs for oritavancin were within 1 doubling dilution of their respective planktonic broth MICs, highlighting the potency of oritavancin against biofilms. These results demonstrate a significant activity of oritavancin against S. aureus in phases of growth that exhibit tolerance to other antimicrobial agents.

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Efficacy of Oritavancin in a Murine Model of Bacillus anthracis Spore Inhalation Anthrax

Antimicrobial Agents and Chemotherapy, 2008

The inhaled form of Bacillus anthracis infection may be fatal to humans. The current standard of ... more The inhaled form of Bacillus anthracis infection may be fatal to humans. The current standard of care for inhalational anthrax postexposure prophylaxis is ciprofloxacin therapy twice daily for 60 days. The potent in vitro activity of oritavancin, a semisynthetic lipoglycopeptide, against B . anthracis (MIC against Ames strain, 0.015 μg/ml) prompted us to test its efficacy in a mouse aerosol-anthrax model. In postexposure prophylaxis dose-ranging studies, a single intravenous (i.v.) dose of oritavancin of 5, 15, or 50 mg/kg 24 h after a challenge with 50 to 75 times the median lethal dose of Ames strain spores provided 40, 70, and 100% proportional survival, respectively, at 30 days postchallenge. Untreated animals died within 4 days of challenge, whereas 90% of control animals receiving ciprofloxacin at 30 mg/kg intraperitoneally twice daily for 14 days starting 24 h after challenge survived. Oritavancin demonstrated significant activity post symptom development; a single i.v. dose ...

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In Vitro Activity of Tebipenem (SPR859) against Penicillin-Binding Proteins of Gram-Negative and Gram-Positive Bacteria

Antimicrobial Agents and Chemotherapy, 2019

Tebipenem (SPR859) is the microbiologically active form of SPR994 (tebipenem-pivoxil), an orally ... more Tebipenem (SPR859) is the microbiologically active form of SPR994 (tebipenem-pivoxil), an orally available carbapenem with activity against extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae . Measurement of the relative binding of SPR859 to the bacterial cell targets revealed that it is a potent inhibitor of multiple penicillin-binding proteins (PBPs) but primarily a Gram-negative PBP 2 inhibitor, similar to other compounds in this class.

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Comparative In Vitro Activity Profile of Oritavancin against Recent Gram-Positive Clinical Isolates

Antimicrobial Agents and Chemotherapy, 2009

Oritavancin activity was tested against 15,764 gram-positive isolates collected from 246 hospital... more Oritavancin activity was tested against 15,764 gram-positive isolates collected from 246 hospital centers in 25 countries between 2005 and 2008. Organisms were Staphylococcus aureus (n = 9,075), coagulase-negative staphylococci (n = 1,664), Enterococcus faecalis (n = 1,738), Enterococcus faecium (n = 819), Streptococcus pyogenes (n = 959), Streptococcus agalactiae (n = 415), group C, G, and F streptococci (n = 84), and Streptococcus pneumoniae (n = 1,010). Among the evaluated staphylococci, 56.7% were resistant to oxacillin. The vancomycin resistance rate among enterococci was 21.2%. Penicillin-resistant and -intermediate rates were 14.7% and 21.4%, respectively, among S. pneumoniae isolates. Among nonpneumococcal streptococci, 18.5% were nonsusceptible to erythromycin. Oritavancin showed substantial in vitro activity against all organisms tested, regardless of resistance profile. The maximum oritavancin MIC against all staphylococci tested (n = 10,739) was 4 μg/ml; the MIC90 agains...

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Screening for Modulators of Biomolecules

In Vitro Activity Analysis of a New Polymyxin, SPR741, Tested in Combination with Antimicrobial Agents against a Challenge Set of Enterobacteriaceae , Including Molecularly Characterized Strains

Antimicrobial Agents and Chemotherapy, 2020

The activities of azithromycin, fusidic acid, vancomycin, doxycycline, and minocycline were evalu... more The activities of azithromycin, fusidic acid, vancomycin, doxycycline, and minocycline were evaluated alone and in combination with SPR741. A total of 202 Escherichia coli and 221 Klebsiella pneumoniae isolates were selected, and they included a genome-sequenced subset ( n = 267), which was screened in silico for β-lactamase, macrolide-lincosamide-streptogramin (MLS), and tetracycline ( tet ) genes. Azithromycin (>16 mg/liter), fusidic acid (>64 mg/liter), vancomycin (>16 mg/liter), and SPR741 (>8 mg/liter) showed off-scale MICs when each was tested alone against all isolates.

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Polymyxins Targeting the Outer Membrane of Gram-negative Bacteria

1304. Characterization of Tebipenem Pivoxil Hydrobromide Pharmacokinetics-Pharmacodynamics (PK-PD) in a Neutropenic Murine Acute Pyelonephritis (AP) Model

Open Forum Infectious Diseases, 2020

Background Tebipenem pivoxil hydrobromide (tebipenem HBr), an orally (PO) bioavailable prodrug of... more Background Tebipenem pivoxil hydrobromide (tebipenem HBr), an orally (PO) bioavailable prodrug of tebipenem, is a carbapenem with broad-spectrum activity against Gram-positive and -negative bacteria that is being developed for the treatment of patients with complicated urinary tract infections, including AP. Data from a one-compartment in vitro infection model demonstrated that the ratio of free-drug plasma area under the curve (AUC) to MIC with adjustment for dosing interval (τ) (AUC:MIC ratio•1/τ) was the PK-PD index most associated with tebipenem HBr efficacy [VanScoy BD et al., IDWeek 2019, Poster 1565]. Studies were undertaken to characterize the magnitude of tebipenem HBr free-drug plasma AUC:MIC ratio•1/τ associated with efficacy for Enterobacteriaceae using a neutropenic murine AP model. Methods A single dose pharmacokinetic study was completed in neutropenic mice infected via intra-renal injection with 104 CFU/kidney of Escherichia coli NCTC 13441. Following PO administrati...

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Pharmacodynamics of Tebipenem: New Options for Oral Treatment of Multi-Drug Resistant Gram-Negative Infections

Antimicrobial Agents and Chemotherapy, 2019

Tebipenem pivoxil HBr (TBPM-PI-HBr) is a novel orally bioavailable carbapenem. The active moiety ... more Tebipenem pivoxil HBr (TBPM-PI-HBr) is a novel orally bioavailable carbapenem. The active moiety is tebipenem. Tebipenem pivoxil is licenced in Japan for children with ear nose and throat infections and respiratory infections. The HBr salt was designed to improve drug substance and drug product properties including stability. TBPM-PI-HBr is now being developed as an agent for the treatment of complicated urinary tract infections (cUTI) in adults. The pharmacokinetics-pharmacodynamics of TBPM-PI-HBr were studied in a well characterized neutropenic murine thigh infection model. Plasma drug concentrations were measured using LC/MS/MS. Dose fractionation experiments were performed after establishing dose-response relationships. The magnitude of drug exposure required for stasis was established using 11 strains of Enterobacteriaceae (Escherichia coli; n=6, Klebsiella pneumoniae; n=5) with a variety of resistance mechanisms. The relationship between drug exposure and the emergence of resi...

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Methods for Evaluation of Antimicrobial Targets

Effect of Polysorbate 80 on Oritavancin Binding to Plastic Surfaces: Implications for Susceptibility Testing

Antimicrobial Agents and Chemotherapy, 2008

Oritavancin, a semisynthetic lipoglycopeptide with activity against gram-positive bacteria, has m... more Oritavancin, a semisynthetic lipoglycopeptide with activity against gram-positive bacteria, has multiple mechanisms of action, including the inhibition of cell wall synthesis and the perturbation of the membrane potential. Approved guidelines for broth microdilution MIC assays with dalbavancin, another lipoglycopeptide, require inclusion of 0.002% polysorbate 80. To investigate the potential impact of polysorbate 80 on oritavancin susceptibility assays, we quantified the recovery of [14C]oritavancin from susceptibility assay plates with and without polysorbate 80 and examined the effect of the presence of polysorbate 80 on the oritavancin MICs for 301 clinical isolates from the genera Staphylococcus, Enterococcus, and Streptococcus. In the absence of polysorbate 80, [14C]oritavancin was rapidly lost from solution in susceptibility assay test plates: 9% of the input drug was recovered in broth at 1 h when [14C]oritavancin was tested at 1 μg/ml. Furthermore, proportionately greater lo...

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Oritavancin Disrupts Membrane Integrity of Staphylococcus aureus and Vancomycin-Resistant Enterococci To Effect Rapid Bacterial Killing

Antimicrobial Agents and Chemotherapy, 2010

Oritavancin is an investigational lipoglycopeptide in clinical development for the treatment of a... more Oritavancin is an investigational lipoglycopeptide in clinical development for the treatment of acute bacterial skin and skin structure infections. In this study, we demonstrate that oritavancin causes bacterial membrane depolarization and permeabilization leading to cell death of Gram-positive pathogens and that these effects are attributable to the 4′-chlorobiphenylmethyl group of the molecule.

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Assessment by Time-Kill Methodology of the Synergistic Effects of Oritavancin in Combination with Other Antimicrobial Agents against Staphylococcus aureus

Antimicrobial Agents and Chemotherapy, 2008

Oritavancin is a semisynthetic lipoglycopeptide in clinical development for serious gram-positive... more Oritavancin is a semisynthetic lipoglycopeptide in clinical development for serious gram-positive infections. This study describes the synergistic activity of oritavancin in combination with gentamicin, linezolid, moxifloxacin, or rifampin in time-kill studies against methicillin-susceptible, vancomycin-intermediate, and vancomycin-resistant Staphylococcus aureus.

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Molecular basis of the non-beta-lactamase-mediated resistance to beta-lactam antibiotics in strains of Haemophilus influenzae isolated in Canada

Antimicrobial Agents and Chemotherapy, 1992

A study recently conducted across Canada showed that 64 of 2,503 clinical isolates of Haemophilus... more A study recently conducted across Canada showed that 64 of 2,503 clinical isolates of Haemophilus influenzae were resistant to beta-lactams without production of a beta-lactamase (L. D. Tremblay, J. L'Ecuyer, P. Provencher, M. G. Bergeron, and Canadian Study Group, Can. Med. Assoc. J. 143:895-900, 1990). The beta-lactamase-negative strains formed three distinct groups, with ampicillin MICs of 0.5 to 1, 2 to 4, and greater than or equal to 8 micrograms/ml for groups I, II, and III, respectively. We have investigated the mechanisms of resistance for eight strains originating from different infections and geographic areas. These strains were representative of groups I to III. Five strains were nontypeable, two were type B, and one was non-B. Chromosomal DNA extracted from each strain was used to transform the laboratory strain Rd. Transformants were selected on beta-lactam-containing plates and showed the same level of resistance to ampicillin as the donor strains. Differences in o...

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Oritavancin Kills Stationary-Phase and Biofilm Staphylococcus aureus Cells In Vitro

Antimicrobial Agents and Chemotherapy, 2008

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1281. An Evaluation of Tebipenem In Vitro Activity Against a Panel of Pseudomonas aeruginosa Isolates with Efflux, AmpC, and OprD Mutations

Open Forum Infectious Diseases, 2021

Background SPR994 is an orally bioavailable pivoxil hydrobromide prodrug of tebipenem, a novel or... more Background SPR994 is an orally bioavailable pivoxil hydrobromide prodrug of tebipenem, a novel oral carbapenem with activity against Gram-positive and -negative bacteria currently under development for the treatment of urinary tract infections (UTI). Pseudomonas aeruginosa has become one of the most common pathogens associated with nosocomial infections. A series of susceptibility studies was designed to evaluate the activity of tebipenem against a panel of P. aeruginosa isolates known to have alterations in efflux pumps, outer-membrane porins, and expression of AmpC beta-lactamase enzymes compared to a subset of wild-type organisms. Methods A panel of 20 P. aeruginosa isolates was subjected to tebipenem and five other challenge compounds (meropenem, ertapenem, levofloxacin, tetracycline, and carbenicillin) in order to determine minimum inhibitory concentration (MIC) values, in triplicate, using standard agar dilution methodologies. P. aeruginosa ATCC 27853 was used as an internal c...

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Epidemiological typing of Moraxella catarrhalis by using DNA probes

Small-fragment restriction enzyme analysis and DNA-DNA hybridization were used to compare 60 stra... more Small-fragment restriction enzyme analysis and DNA-DNA hybridization were used to compare 60 strains of Moraxella catarrhalis isolated from various geographic locations. Restriction enzyme analysis with HaeIII resulted in 46 different patterns, 7 of which were shared by more than one isolate. Hybridizations with two DNA probes resulted in 18 different patterns, 11 of which were shared by more than one isolate. Strains with the same restriction enzyme pattern always had the same hybridization pattern. However, of the 50 strains that shared the 11 hybridization patterns, 39 could be further differentiated by restriction enzyme analysis. We found that hybridization is a method that is specific for the epidemiological typing ofM. catarrhalis, but because of limited sensitivity, combination with small-fragment restriction enzyme analysis may be necessary to better determine the relatedness of strains.

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Tebipenem, the first oral carbapenem antibiotic

Expert review of anti-infective therapy, 2018

Infections caused by antibiotic-resistant pathogens, particularly Gram-negative bacteria, have be... more Infections caused by antibiotic-resistant pathogens, particularly Gram-negative bacteria, have become increasingly challenging to successfully treat. The beta-lactam antibiotic subclass, the carbapenems, have proven valuable for the treatment of such Gram-negative bacterial infections due to their spectrum and β-lactamase stability properties. However, all marketed carbapenems to date are parenterally administered to adult patients. Areas covered: One carbapenem, tebipenem-pivoxil (TBPM-PI), is an oral prodrug that was approved in Japan for pediatric use only in 2009. This review summarizes preclinical and clinical data for TBPM-PI, which is now in clinical development again this time for use as the first oral carbapenem available for treatment of bacterial infections in adult patients. Expert commentary: There is an urgent unmet need with an increasing prevalence of fluoroquinolone-resistant and ESBL-producing Gram-negative pathogens in the hospital and community setting. Carbapene...

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