scholarly journals Frequency and Mechanism of Spontaneous Resistance to Sulbactam Combined with the Novel β-Lactamase Inhibitor ETX2514 in Clinical Isolates of Acinetobacter baumannii

2017 ◽  
Vol 62 (2) ◽  
Author(s):  
Sarah M. McLeod ◽  
Adam B. Shapiro ◽  
Samir H. Moussa ◽  
Michele Johnstone ◽  
Robert E. McLaughlin ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Broad Spectrum ◽  
Active Site ◽  
Stringent Response ◽  
Clinical Isolates ◽  
The Novel ◽  
Penicillin Binding Protein ◽  
Content Type ◽  
Sensitive Isolate ◽  
Lactamase Inhibitor

ABSTRACTThe novel diazabicyclooctenone ETX2514 is a potent, broad-spectrum serine β-lactamase inhibitor that restores sulbactam activity against resistantAcinetobacter baumannii. The frequency of spontaneous resistance to sulbactam-ETX2514 in clinical isolates was found to be 7.6 × 10−10to <9.0 × 10−10at 4× MIC and mapped to residues near the active site of penicillin binding protein 3 (PBP3). Purified mutant PBP3 proteins demonstrated reduced affinity for sulbactam. In a sulbactam-sensitive isolate, resistance also mapped to stringent response genes associated with resistance to PBP2 inhibitors, suggesting that in addition to β-lactamase inhibition, ETX2514 may enhance sulbactam activity inA. baumanniivia inhibition of PBP2.

scholarly journals In Vitro Activity of the Ultra-Broad-Spectrum Beta-Lactamase Inhibitor QPX7728 in Combination with Meropenem against Clinical Isolates of Carbapenem-Resistant Acinetobacter baumannii

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
Kirk Nelson ◽  
Debora Rubio-Aparicio ◽  
Ruslan Tsivkovski ◽  
Dongxu Sun ◽  
Maxim Totrov ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Broad Spectrum ◽  
Wide Distribution ◽  
Clinical Isolates ◽  
Beta Lactamase ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Substrate Inhibitor ◽  
Lactamase Inhibitor

ABSTRACT QPX7728 is a recently discovered ultra-broad-spectrum beta-lactamase inhibitor (BLI) with potent inhibition of key serine and metallo-beta-lactamases. QPX7728 enhances the potency of many beta-lactams, including carbapenems, in beta-lactamase-producing Gram-negative bacteria, including Acinetobacter spp. The potency of meropenem alone and in combination with QPX7728 (1 to 16 μg/ml) was tested against 275 clinical isolates of Acinetobacter baumannii (carbapenem-resistant A. baumannii [CRAB]) collected worldwide that were highly resistant to carbapenems (MIC50 and MIC90 for meropenem, 64 and >64 μg/ml). Addition of QPX7728 resulted in a marked concentration-dependent increase in meropenem potency, with the MIC90 of meropenem alone decreasing from >64 μg/ml to 8 and 4 μg/ml when tested with fixed concentrations of QPX7728 at 4 and 8 μg/ml, respectively. In order to identify the mechanisms that modulate the meropenem-QPX7728 MIC, the whole-genome sequences were determined for 135 isolates with a wide distribution of meropenem-QPX7728 MICs. This panel of strains included 116 strains producing OXA carbapenemases (71 OXA-23, 16 OXA-72, 16 OXA-24, 9 OXA-58, and 4 OXA-239), 5 strains producing NDM-1, one KPC-producing strain, and 13 strains that did not carry any known carbapenemases but were resistant to meropenem (MIC ≥ 4 μg/ml). Our analysis indicated that mutated PBP3 (with mutations localized in the vicinity of the substrate/inhibitor binding site) is the main factor that contributes to the reduction of meropenem-QPX7728 potency. Still, >90% of isolates that carried PBP3 mutations remained susceptible to ≤8 μg/ml of meropenem when tested with a fixed 4 to 8 μg/ml of QPX7728. In the absence of PBP3 mutations, the MICs of meropenem tested in combination with 4 to 8 μg/ml of QPX7728 did not exceed 8 μg/ml. In the presence of both PBP3 and efflux mutations, 84.6% of isolates were susceptible to ≤8 μg/ml of meropenem with 4 or 8 μg/ml of QPX7728. The combination of QPX7728 with meropenem against CRAB isolates with multiple resistance mechanisms has an attractive microbiological profile.

scholarly journals Iron Restriction to Clinical Isolates ofCandida albicansby the Novel Chelator DIBI Inhibits Growth and Increases Sensitivity to AzolesIn VitroandIn Vivoin a Murine Model of Experimental Vaginitis

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Kimberley A. Savage ◽  
Maria del Carmen Parquet ◽  
David S. Allan ◽  
Ross J. Davidson ◽  
Bruce E. Holbein ◽  
...  
Keyword(s):  
Iron Homeostasis ◽  
Iron Chelation ◽  
Opportunistic Pathogen ◽  
Clinical Isolates ◽  
Cell Multiplication ◽  
The Novel ◽  
Content Type ◽  
Sensitive Isolate ◽  
Human Infections

ABSTRACTCandida albicansis an important opportunistic pathogen causing various human infections that are often treated with azole antifungals. The U.S. CDC now regards developing candidal antifungal resistance as a threat, creating a need for new and more effective antifungal treatments. Iron is an essential nutrient for all living cells, and there is growing evidence that interference with iron homeostasis ofC. albicanscan improve its response to antifungals. This study was aimed at establishing whether withholding iron by currently used medical iron chelators and the novel chelator DIBI could restrict growth and also enhance the activity of azoles against clinical isolates ofC. albicans. DIBI, but not deferoxamine or deferiprone, inhibited the growth ofC. albicansat relatively low concentrationsin vitro, and this inhibition was reversed by iron addition. DIBI in combination with various azoles demonstrated stronger growth inhibition than the azoles alone and greatly prolonged the inhibition of cell multiplication. In addition, the administration of DIBI along with fluconazole (FLC) to mice inoculated with an FLC-sensitive isolate in a model of experimentalC. albicansvaginitis showed a markedly improved clearance of infection. These results suggest that iron chelation by DIBI has the potential to enhance azole efficacy for the treatment of candidiasis.

scholarly journals PotentIn VitroAntibacterial Activity of DS-8587, a Novel Broad-Spectrum Quinolone, against Acinetobacter baumannii

2013 ◽  
Vol 57 (4) ◽  
pp. 1978-1981 ◽  
Author(s):  
Saito Higuchi ◽  
Yoshikuni Onodera ◽  
Megumi Chiba ◽  
Kazuki Hoshino ◽  
Naomasa Gotoh
Keyword(s):  
Antibacterial Activity ◽  
Acinetobacter Baumannii ◽  
Broad Spectrum ◽  
Inhibitory Activity ◽  
Efflux Pumps ◽  
Single Step ◽  
Clinical Isolates ◽  
Effective Agent ◽  
Content Type

ABSTRACTWe investigated thein vitroactivity of DS-8587, a novel fluoroquinolone, againstAcinetobacter baumannii. The MICs of DS-8587 against clinical isolates and its inhibitory activity against target enzymes were superior to those of ciprofloxacin and levofloxacin. Furthermore, the antibacterial activity of DS-8587 was less affected byadeA/adeB/adeCorabeMefflux pumps than was that of ciprofloxacin and the frequency of single-step mutations with DS-8587 was lower than that with ciprofloxacin. DS-8587 might be an effective agent againstA. baumanniiinfection.

scholarly journals VNRX-5133 (Taniborbactam), a Broad-Spectrum Inhibitor of Serine- and Metallo-β-Lactamases, Restores Activity of Cefepime in Enterobacterales and Pseudomonas aeruginosa

2019 ◽  
Vol 64 (3) ◽  
Author(s):  
Jodie C. Hamrick ◽  
Jean-Denis Docquier ◽  
Tsuyoshi Uehara ◽  
Cullen L. Myers ◽  
David A. Six ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibacterial Activity ◽  
Broad Spectrum ◽  
Active Site ◽  
Competitive Inhibitor ◽  
Clinical Isolates ◽  
Active Site Residues ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Reversible Covalent

ABSTRACT As shifts in the epidemiology of β-lactamase-mediated resistance continue, carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) are the most urgent threats. Although approved β-lactam (BL)–β-lactamase inhibitor (BLI) combinations address widespread serine β-lactamases (SBLs), such as CTX-M-15, none provide broad coverage against either clinically important serine-β-lactamases (KPC, OXA-48) or clinically important metallo-β-lactamases (MBLs; e.g., NDM-1). VNRX-5133 (taniborbactam) is a new cyclic boronate BLI that is in clinical development combined with cefepime for the treatment of infections caused by β-lactamase-producing CRE and CRPA. Taniborbactam is the first BLI with direct inhibitory activity against Ambler class A, B, C, and D enzymes. From biochemical and structural analyses, taniborbactam exploits substrate mimicry while employing distinct mechanisms to inhibit both SBLs and MBLs. It is a reversible covalent inhibitor of SBLs with slow dissociation and a prolonged active-site residence time (half-life, 30 to 105 min), while in MBLs, it behaves as a competitive inhibitor, with inhibitor constant (Ki) values ranging from 0.019 to 0.081 μM. Inhibition is achieved by mimicking the transition state structure and exploiting interactions with highly conserved active-site residues. In microbiological testing, taniborbactam restored cefepime activity in 33/34 engineered Escherichia coli strains overproducing individual enzymes covering Ambler classes A, B, C, and D, providing up to a 1,024-fold shift in the MIC. Addition of taniborbactam restored the antibacterial activity of cefepime against all 102 Enterobacterales clinical isolates tested and 38/41 P. aeruginosa clinical isolates tested with MIC90s of 1 and 4 μg/ml, respectively, representing ≥256- and ≥32-fold improvements, respectively, in antibacterial activity over that of cefepime alone. The data demonstrate the potent, broad-spectrum rescue of cefepime activity by taniborbactam against clinical isolates of CRE and CRPA.

scholarly journals In VitroActivity of the New β-Lactamase Inhibitors Relebactam and Vaborbactam in Combination with β-Lactams againstMycobacterium abscessusComplex Clinical Isolates

2019 ◽  
Vol 63 (3) ◽  
Author(s):  
Amit Kaushik ◽  
Nicole C. Ammerman ◽  
Jin Lee ◽  
Olumide Martins ◽  
Barry N. Kreiswirth ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Multidrug Resistant ◽  
Mycobacterium Abscessus ◽  
Clinical Isolates ◽  
Phase Iii ◽  
Intrinsic Resistance ◽  
Content Type ◽  
Phase Iii Trials ◽  
Lactamase Inhibitor

ABSTRACTPulmonary disease due to infection withMycobacterium abscessuscomplex (MABC) is notoriously difficult to treat, in large part due to the intrinsic resistance of MABC strains to most antibiotics, including β-lactams. MABC organisms express a broad-spectrum β-lactamase that is resistant to traditional β-lactam-based β-lactamase inhibitors but inhibited by a newer non-β-lactam-based β-lactamase inhibitor, avibactam. Consequently, the susceptibility of MABC members to some β-lactams is increased in the presence of avibactam. Therefore, we hypothesized that two new non-β-lactam-based β-lactamase inhibitors, relebactam and vaborbactam, would also increase the susceptibility of MABC organisms to β-lactams. The objective of the present study was to evaluate thein vitroactivity of various marketed β-lactams alone and in combination with either relebactam or vaborbactam against multidrug-resistant MABC clinical isolates. Our data demonstrate that both β-lactamase inhibitors significantly improved the anti-MABC activity of many carbapenems (including imipenem and meropenem) and cephalosporins (including cefepime, ceftaroline, and cefuroxime). As a meropenem-vaborbactam combination is now marketed and an imipenem-relebactam combination is currently in phase III trials, these fixed combinations may become the β-lactams of choice for the treatment of MABC infections. Furthermore, given the evolving interest in dual β-lactam regimens, our results identify select cephalosporins, such as cefuroxime, with superior activity in the presence of a β-lactamase inhibitor that are deserving of further evaluation in combination with these carbapenem–β-lactamase inhibitor products.

scholarly journals Septal Class A Penicillin-Binding Protein Activity and LD-Transpeptidases Mediate Selection of Colistin-Resistant Lipooligosaccharide-Deficient Acinetobacter baumannii

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Katie N. Kang ◽  
Misha I. Kazi ◽  
Jacob Biboy ◽  
Joe Gray ◽  
Hannah Bovermann ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Binding Protein ◽  
Clinical Isolates ◽  
Compensatory Mutation ◽  
Penicillin Binding Protein ◽  
Gram Negative ◽  
Content Type ◽  
Class A ◽  
The Impact ◽  
Selection Of

ABSTRACT Despite dogma suggesting that lipopolysaccharide/lipooligosaccharide (LOS) was essential for viability of Gram-negative bacteria, several Acinetobacter baumannii clinical isolates produced LOS− colonies after colistin selection. Inactivation of the conserved class A penicillin-binding protein, PBP1A, was a compensatory mutation that supported isolation of LOS− A. baumannii, but the impact of PBP1A mutation was not characterized. Here, we show that the absence of PBP1A causes septation defects and that these, together with ld-transpeptidase activity, support isolation of LOS− A. baumannii. PBP1A contributes to proper cell division in A. baumannii, and its absence induced cell chaining. Only isolates producing three or more septa supported selection of colistin-resistant LOS− A. baumannii. PBP1A was enriched at the midcell, where the divisome complex facilitates daughter cell formation, and its localization was dependent on glycosyltransferase activity. Transposon mutagenesis showed that genes encoding two putative ld-transpeptidases (LdtJ and LdtK) became essential in the PBP1A mutant. Both LdtJ and LdtK were required for selection of LOS− A. baumannii, but each had distinct enzymatic activities in the cell. Together, these findings demonstrate that defects in PBP1A glycosyltransferase activity and ld-transpeptidase activity remodel the cell envelope to support selection of colistin-resistant LOS− A. baumannii. IMPORTANCE The increasing prevalence of antibiotic treatment failure associated with Gram-negative bacterial infections highlights an urgent need to develop new alternative therapeutic strategies. The last-line antimicrobial colistin (polymyxin E) targets the ubiquitous outer membrane lipopolysaccharide (LPS)/LOS membrane anchor, lipid A, which is essential for viability of most diderms. However, several LOS− Acinetobacter baumannii clinical isolates were recovered after colistin selection, suggesting a conserved resistance mechanism. Here, we characterized a role for penicillin-binding protein 1A in A. baumannii septation and intrinsic β-lactam susceptibility. We also showed that defects in PBP1A glycosyltransferase activity and ld-transpeptidase activity support isolation of colistin-resistant LOS− A. baumannii.

scholarly journals Complete Genome Sequences of Four Extensively Drug-Resistant Acinetobacter baumannii Isolates from Thailand

2020 ◽  
Vol 9 (40) ◽  
Author(s):  
Peechanika Chopjitt ◽  
Thidathip Wongsurawat ◽  
Piroon Jenjaroenpun ◽  
Parichart Boueroy ◽  
Rujirat Hatrongjit ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Complete Genome ◽  
Sequence Type ◽  
Clinical Isolates ◽  
Drug Resistant ◽  
Genome Sequences ◽  
Content Type ◽  
Type Isolate ◽  
Resistant Genes ◽  
Extensively Drug Resistant

ABSTRACT Here, we report the complete genome sequences of four clinical isolates of extensively drug-resistant Acinetobacter baumannii (XDRAB), isolated in Thailand. These results revealed multiple antimicrobial-resistant genes, each involving two sequence type 16 (ST16) isolates, ST2, and a novel sequence type isolate, ST1479.

scholarly journals Activity of Meropenem-Vaborbactam againstPseudomonas aeruginosaandAcinetobacter baumanniiin a Neutropenic Mouse Thigh Infection Model

2018 ◽  
Vol 63 (1) ◽  
Author(s):  
Mojgan Sabet ◽  
Ziad Tarazi ◽  
David C. Griffith
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Acinetobacter Baumannii ◽  
Clinical Isolates ◽  
Infection Model ◽  
Model Data ◽  
Bacterial Killing ◽  
Content Type

ABSTRACTWe have evaluated the activity of meropenem-vaborbactam against clinical isolates ofPseudomonas aeruginosaandAcinetobacter baumanniiin a neutropenic mouse thigh infection model. Data show that meropenem-vaborbactam regimens equivalent to 3-h infusions every 8 h with 2 g meropenem and 2 g vaborbactam produced bacterial killing against strains with MICs of 2 to 16 mg/liter and suggests that this combination may have utility in the treatment of infections caused byP. aeruginosaandA. baumannii.

scholarly journals A Prospective Study of Acinetobacter baumannii Complex Isolates and Colistin Susceptibility Monitoring by Mass Spectrometry of Microbial Membrane Glycolipids

2018 ◽  
Vol 57 (3) ◽  
Author(s):  
Lisa M. Leung ◽  
Christi L. McElheny ◽  
Francesca M. Gardner ◽  
Courtney E. Chandler ◽  
Sarah L. Bowler ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Acinetobacter Baumannii ◽  
Lipid A ◽  
Membrane Lipids ◽  
Clinical Isolates ◽  
Colistin Resistance ◽  
Hospital System ◽  
Content Type ◽  
Acinetobacter Baumannii Complex ◽  
Gram Negative Organisms

ABSTRACT Acinetobacter baumannii is a prevalent nosocomial pathogen with a high incidence of multidrug resistance. Treatment of infections due to this organism with colistin, a last-resort antibiotic of the polymyxin class, can result in the emergence of colistin-resistant strains. Colistin resistance primarily occurs via modifications of the terminal phosphate moieties of lipopolysaccharide-derived lipid A, which reduces overall membrane electronegativity. These modifications are readily identified by mass spectrometry (MS). In this study, we prospectively collected Acinetobacter baumannii complex clinical isolates from a hospital system in Pennsylvania over a 3-year period. All isolates were evaluated for colistin resistance using standard MIC testing by both agar dilution and broth microdilution, as well as genospecies identification and lipid A profiling using MS analyses. Overall, an excellent correlation between colistin susceptibility and resistance, determined by MIC testing, and the presence of a lipid A modification, determined by MS, was observed with a sensitivity of 92.9% and a specificity of 94.0%. Additionally, glycolipid profiling was able to differentiate A. baumannii complex organisms based on their membrane lipids. With the growth of MS use in clinical laboratories, a reliable MS-based glycolipid phenotyping method that identifies colistin resistance in A. baumannii complex clinical isolates, as well as other Gram-negative organisms, represents an alternative or complementary approach to existing diagnostics.

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