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PubMed1991

Outer membrane permeability of Acinetobacter calcoaceticus and its implication in antibiotic resistance.

In order to understand high and broad antibiotic resistance of Acinetobacter calcoaceticus, the outer membrane permeability was studied. The permeability coefficients of zwitterionic cephalosporins in the intact cell outer membrane were 0.14-1.12 x 10(-4) cm3/min/mg protein. These values were two to seven times lower than the permeability coefficients of the same beta-lactams in the outer membrane of Pseudomonas aeruginosa. The diffusion rates of carbapenems and zwitterionic cephalosporins into liposomes containing purified outer membrane appeared to be about 1-3%, that of the Escherichia coli B outer membrane. These results indicate that the outer membrane of A. calcoaceticus acts as a substantial barrier against the penetration of these antibiotics. About 80 times of the A. calcoaceticus outer membrane was needed in the liposome compared with E. coli B to show the same extent of saccharide permeability. Two minor outer membrane proteins (less than 5% of total outer membrane protein) were identified to be the porins. These results suggest that one of the causes for the high antibiotic resistance of A. calcoaceticus is attributable to the presence of a small number of small-sized porins.

Acinetobacter calcoaceticus↗
PubMed1991

Mechanisms of resistance to beta-lactam antibiotics in Acinetobacter calcoaceticus.

Examination of 12 strains of Acinetobacter calcoaceticus revealed that the strains expressed different constitutive levels of beta-lactamase. Mutants resistant to cefoxitin, cefoperazone or ceftazidime were selected from a strain producing a low level of beta-lactamase. All the mutants showed no change in expression of beta-lactamase, but produced penicillin-binding proteins with altered expression and/or affinity for beta-lactams. In addition, the outer membrane of the mutants showed decreased permeability (40-80% that of the parent strain) towards small hydrophilic solutes, together with diminished production of a 46.5 kDa porin protein. It was concluded that the enhanced resistance to beta-lactams in the A. calcoaceticus mutants was the result of interplay between the altered penicillin binding proteins and the reduced outer membrane permeability.

Acinetobacter calcoaceticus↗
PubMed1994

High level kanamycin resistance associated with the hyperproduction of AAC(3)II and a generalised reduction in the accumulation of aminoglycosides in Acinetobacter spp.

The clinical isolate of Acinetobacter baumannii strain SAK contains an actively transcribed aacC2 gene and a latent aadB gene that encode the aminoglycoside-modifying enzymes, AAC(3)II and AAD(2"), respectively. In an attempt to activate the aadB gene, the strain was cultured in the presence of kanamycin which is a substrate for AAD(2"). Although it was possible to isolate kanamycin resistant derivatives these were not associated with detectable AAD(2") activity. Instead, there was a marked increase in the level of AAC(3)II activity which was associated with amplification of the aacC2 gene.

Acinetobacter↗
PubMed1996

In-vitro activity of cephalosporins alone and combined with sulbactam against various strains of Acinetobacter baumannii with different antibiotic resistance profiles.

The beta-lactamases of six strains of Acinetobacter baumannii were investigated using analytical isoelectric focusing, and the MIC values for 16 beta-lactam antibiotics determined against the strains. Three strains produced a chromosomal cephalosporinase (pI > 8.5), one strain a CARB-5 beta-lactamase (pI = 6.35), one strain a TEM-1 penicillinase (pI = 5.4) as well as a cephalosporinase (pI > 8.5), and one carbapenem-resistant strain a beta-lactamase with a pI > 8.5. Ceftazidime, cefepime, cefpirome, imipenem and meropenem were found to be the most effective beta-lactams against five strains. Sulbactam was active against four of the strains at 1-4 mg/L and showed enhanced killing effects with cefpirome.

Acinetobacter↗
PubMed1996

Imipenem resistance among Acinetobacter baumannii: association with reduced expression of a 33-36 kDa outer membrane protein.

The mechanism of imipenem resistance of two Acinetobacter baumannii isolates (A-1 and A-24) was characterized in this study. A spontaneous revertant (A-1 (rev)) derived from isolate A-1 showed susceptibility to imipenem. beta-Lactamase hydrolysis studies showed no evidence of an imipenem hydrolyzing enzyme among A-1, A-24, A-1 (rev), or two other imipenem susceptible A. baumannii isolates. Outer membrane protein (OMP) analysis indicated decreased expression of a 33-36 kDa protein by isolates A-1 and A-24 when compared with A-1 (rev) and the other A. baumannii isolates. In conclusion, decreased expression of a 33-36 kDa OMP is associated with imipenem resistance among A. baumannii.

Acinetobacter↗
PubMed1996

Characterisation of DNA gyrase and measurement of drug accumulation in clinical isolates of Acinetobacter baumannii resistant to fluoroquinolones.

Twelve clinical isolates of Acinetobacter baumannii highly resistant to pefloxacin (MIC > or = 32 mg/L) and to ciprofloxacin (MIC > or = 16 mg/L), were studied. A susceptible isolate used as a reference (MIC of 0.032 and 0.25 mg/L for ciprofloxacin and pefloxacin, respectively) accumulated 85 mg of pefloxacin per litre of cell volume within 10 min, from a solution containing 10 mg/L of antibiotic. One resistant isolate accumulated the same amount of pefloxacin, while the 11 others accumulated between 40 and 70 mg/L of cell volume. The differences between reference and resistant isolates with respect to ciprofloxacin and sparfloxacin accumulation were less pronounced. There were no apparent differences in the outer membrane protein profiles of susceptible and resistant isolates. DNA gyrase was isolated from four A. baumannii and the minimum concentration of fluoroquinolones, required to inhibit gyrase-catalysed supercoiling of plasmid DNA was 5- to 80-fold higher for the resistant isolates than for the reference strain. Although most isolates showed some degree of reduced fluoroquinolone accumulation, a DNA gyrase mutation was more likely to be the main mechanism of the high level resistance encountered.

Acinetobacter↗
PubMed1997

Quinolone-resistance mutations in the topoisomerase IV parC gene of Acinetobacter baumannii.

Mutations in the parC gene, which encodes a subunit of topoisomerase IV, were determined in 21 epidemiologically unrelated clinical isolates of Acinetobacter baumannii. Our studies highlight the conserved sequences in the quinolone-resistance-determining region of the parC gene from A. baumannii and other bacteria. Nine of ten isolates with MICs of ciprofloxacin of > or = 32 mg/L showed a change of Ser80 to Leu and one showed a change of Glu84 to Lys. These results suggest that ParC from A. baumannii is a secondary target for quinolones and that mutations at residues Ser80 and Glu84, when combined with mutations at Ser83 of GyrA, may render A. baumannii highly resistant to quinolones.

Acinetobacter↗
PubMed1999

Biochemical characteristics of a carbapenemase from an Acinetobacter baumannii isolate collected in Buenos Aires, Argentina.

Three carbapenem-resistant Acinetobacter baumannii isolates were collected at a hospital in Buenos Aires, Argentina. Isoelectric focusing revealed multiple beta-lactamases, with two of the isolates showing identical profiles. A pI 6.9 carbapenemase with a molecular weight of 30 kDa was purified from one of these two isolates. The enzyme was predominantly a penicillinase, with its highest Vmax for oxacillin but highest Vmax/Km for benzylpenicillin. First-generation cephalosporins and imipenem were weaker substrates than penicillins, and oxyimino-aminothiazolyl cephalosporins were essentially stable. Meropenem-hydrolysing activity was not detected, despite resistance. The carbapenemase was inhibited by clavulanic acid and tazobactam, but not by EDTA. These kinetics place the enzyme into functional group 2; as an oxacillinase it could be placed in sub-group 2d or, as a zinc-independent carbapenemase, in sub-group 2f.

Acinetobacter↗
PubMed2000

Comparative activities of polycationic peptides and clinically used antimicrobial agents against multidrug-resistant nosocomial isolates of Acinetobacter baumannii.

The in vitro activity of buforin II, cecropin P1, indolicidin, magainin II and ranalexin, alone and in combination with eight clinically used antimicrobial agents was investigated against 12 multidrug-resistant strains of Acinetobacter baumannii isolated from immunocompromised patients. Antimicrobial activities were measured by MIC, MBC and viable count. The peptides had a varied range of inhibitory values: overall, the organisms were more susceptible to buforin II (MIC range 0.25-16 mg/L), cecropin P1 (0.50-32 mg/L) and magainin II (0.50-16 mg/L). Synergy occurred when magainin II was combined with beta-lactam antibiotics.

Acinetobacter↗
PubMed2000

In vivo activity of levofloxacin alone or in combination with imipenem or amikacin in a mouse model of Acinetobacter baumannii pneumonia.

We evaluated the in vivo activity of levofloxacin alone or in combination with imipenem or amikacin in a mouse model of Acinetobacter baumannii pneumonia using a susceptible strain and one with low-level resistance (MIC/MBC of levofloxacin: 0.06/0.06 and 4/4 mg/L, respectively). As demonstrated previously with other pathogens, the AUC/MIC ratio predicted the efficacy of fluoroquinolones against A. baumannii. This parameter correlated with bactericidal effect and survival. Combination therapy did not enhance the efficacy of levofloxacin.

Acinetobacter Infections↗
PubMed2003

Relationship between beta-lactamase production, outer membrane protein and penicillin-binding protein profiles on the activity of carbapenems against clinical isolates of Acinetobacter baumannii.

Twenty blood isolates of Acinetobacter baumannii were studied, representing eight pulsed-field gel electrophoresis patterns and all different antimicrobial susceptibility patterns observed during 1995-97 at the University Hospital Virgen Macarena, Seville, Spain. The MIC(90)s (mg/L) of imipenem and meropenem decreased from 16 to 0.5 and from 8 to 4, respectively, in the presence of BRL 42715 (BRL) but not clavulanic acid. Hydrolysing activity (nmol/min/mg) of bacterial supernatants against cefaloridine ranged from 8.8 to 552.3 for A. baumannii type I (imipenem MICs < or = 2), which expressed only a beta-lactamase of pI > or = 9, and from 12.3 to 1543.5 for A. baumannii type II (imipenem MICs > or = 4), which expressed a beta-lactamase of pI > or = 9 and two others of pI 6.3 and 7. The hydrolysing activities of A. baumannii type II against imipenem, meropenem and oxacillin were higher than those observed for A. baumannii type I. Ten outer membrane protein (OMP) profiles (A. baumannii types I and II) were visualized on 10% SDS-PAGE gels with 6 M urea, whereas only five OMP profiles (A. baumannii types I and II) were differentiated in 12% SDS-PAGE gels. Five A. baumannii with OMP profile type B, characterized by the absence of a 22.5 kDa OMP, were resistant to meropenem and/or imipenem. Twelve penicillin-binding protein (PBP) patterns were observed. PBP patterns of A. baumannii type II were characterized by the absence of a 73.2 kDa band (PBP 2). We concluded that production of beta-lactamases of pI 6.3 and 7.0 and reduced expression of PBP 2 are the most frequently observed mechanisms of resistance to carbapenems. In some isolates, loss of a 22.5 kDa OMP is also related to resistance to carbapenems.

Acinetobacter baumannii↗
PubMed2003

AmpC cephalosporinase hyperproduction in Acinetobacter baumannii clinical strains.

OBJECTIVE: To compare the genetic environments of ampC genes in different Acinetobacter baumannii isolates showing different levels of beta-lactam resistance. METHODS: The patterns of beta-lactam resistance and beta-lactamase production were investigated for 42 A. baumannii clinical strains. The MICs of various beta-lactams were determined in the presence or absence of the class C cephalosporinase inhibitor, cloxacillin (500 mg/L). The ampC gene and its 5' adjacent sequence were analysed by PCR and DNA sequencing. An RT-PCR method was developed to evaluate ampC transcript levels. RESULTS: Strains fell into three resistance groups: first, strains with a ceftazidime MIC < or =8 mg/L (20 strains, 47.6%); secondly, strains with a ceftazidime MIC 32 mg/L, which was reduced four-fold in the presence of cloxacillin (eight strains, 19%); and thirdly, strains with a ceftazidime MIC > or =256 mg/L, which did not decrease in the presence of cloxacillin (14 strains, 33.4%). In all of the resistant isolates (groups II and III), but not in any of the ceftazidime-susceptible isolates (group I), a 1180 bp insert showing all the characteristics of an insertion sequence was detected upstream from the ampC gene. Isolates having this insert overexpress ampC, according to RT-PCR experiments. CONCLUSION: Presence of an insertion sequence upstream of ampC in A. baumannii clinical isolates, possibly including a strong promoter, has the potential to cause over-expression of AmpC, resulting in high-level ceftazidime resistance.

5' Untranslated Regions↗
PubMed2005

Identification of Tet 39, a novel class of tetracycline resistance determinant in Acinetobacter spp. of environmental and clinical origin.

A novel tetracycline resistance determinant named Tet 39 was found in unrelated Acinetobacter strains isolated from freshwater trout farms (n=4) and sewage (n=6) in Denmark, and from a clinical specimen in the Netherlands (n=1). The determinant was located on transferable plasmids and consisted of tetA(39), most likely conferring resistance by active efflux, and a putative repressor gene tetR(39).

Acinetobacter↗
PubMed2006

Studies on the antimicrobial activity of cecropin A-melittin hybrid peptides in colistin-resistant clinical isolates of Acinetobacter baumannii.

OBJECTIVES: Acinetobacter baumannii has successfully developed resistance against all common antibiotics, including colistin, one of the last active drugs against this pathogen. We have tested whether the differences in lethal mechanism between polymyxin B and the cecropin A-melittin hybrid peptide CA(1-8)M(1-18), shown previously with a colistin-susceptible strain, can be exploited as a new chemotherapeutic alternative against colistin-resistant clinical isolates. Furthermore, the effect of capsule on the bactericidal activity of cecropin A-melittin analogues (CAMs) was tested. METHODS: MICs and MBCs of the four CAMs were determined for 13 clinical isolates. The bactericidal activity of the antimicrobial peptides was measured using time-kill curves. The presence or absence of capsule was determined using Indian ink stain. RESULTS: The MIC ranges of CA(1-8)M(1-18) and three of its shortened analogues, namely CA(1-7)M(2-9), its Nalpha-terminal octanoylated analogue and CA(1-7)M(5-9), for A. baumannii strains were 2-8, 2-4, 2-8 and 4-4 mg/L, respectively. MBCs differed by a factor of two at the most. All of the cecropin A-melittin peptides showed bactericidal activity in time-kill curves against four A. baumannii strains. The bactericidal activity of CAMs was not affected by the presence of capsule. CONCLUSIONS: These results indicate that this class of peptides has a fast microbicidal effect on the colistin-resistant A. baumannii isolates, regardless of considerable structural variation among the four peptides and varying colistin MIC for the strains included in the study. Overall, the cecropin A-melittin peptides appear to be a promising alternative to overcome polymyxin resistance in A. baumannii.

Acinetobacter baumannii↗
PubMed2006

Acinetobacter baumannii bloodstream infection while receiving tigecycline: a cautionary report.

OBJECTIVES: Tigecycline has shown in vitro activity against Acinetobacter baumannii. Yet, published clinical experience with tigecycline use outside clinical trials is lacking. We describe, for the first time, bloodstream infection caused by tigecycline-non-susceptible A. baumannii occurring in patients receiving tigecycline for other indications. The possible mechanisms of resistance and pharmacokinetic limitations of the drug are addressed. METHODS: The clinical records of involved patients were systematically reviewed. Tigecycline susceptibility testing was initially performed using the Etest method and confirmed by agar dilution. Involved isolates underwent PFGE and exposure to phenyl-arginine-beta-naphthylamide (PAbetaN), an efflux pump inhibitor. RESULTS: Two patients developed A. baumannii bloodstream infection while receiving tigecycline. Tigecycline was administered for other indications for 9 and 16 days, respectively, before the onset of A. baumannii infection. Patient 1 died of overwhelming A. baumannii infection and Patient 2 recovered after a change in antibiotic therapy. The MICs of tigecycline were 4 and 16 mg/L, respectively. Both isolates had a multidrug-resistant phenotype and were genotypically unrelated. After exposure to PAbetaN, the MICs reduced to 1 and 4 mg/L, respectively. CONCLUSIONS: To our knowledge, this is the first clinical description of bloodstream infection caused by tigecycline-non-susceptible A. baumannii. Such resistance appears to be at least partly attributable to an efflux pump mechanism. Given the reported low serum tigecycline levels, we urge caution when using this drug for treatment of A. baumannii bloodstream infection.

Acinetobacter baumannii↗
PubMed1985

AccIII, a new restriction endonuclease from Acinetobacter calcoaceticus.

A new site-specific restriction endonuclease, AccIII, was isolated from Acinetobacter calcoaceticus. AccIII recognizes T/CCGGA and cleaves at the position shown by the arrow. AccIII activity was inhibited by adenine methylation at the overlapping dam methylase recognition sequence.

Acinetobacter↗
PubMed1986

Acinetobacter calcoaceticus encoded mutarotase: nucleotide sequence analysis of the gene and characterization of its secretion in Escherichia coli.

The nucleotide sequence of the mutarotase gene from Acinetobacter calcoaceticus has been determined. It reveals an open reading frame of 381 amino acids. The codon usage of A. calcoaceticus for this gene is similar to E. coli except for the amino acids Leu, Ala, Glu, and Arg where major differences exist. This did not interfere drastically with high level expression in E. coli. The regulatory sequences for the initiation of translation are similar to the ones described for E. coli. The N-terminal 20 amino acids, which are not found in the mature enzyme, show homology to signal sequences of exported proteins. In A. calcoaceticus and E. coli mutarotase is specifically secreted into the periplasmic space. Processing of the signal sequence occurs at identical sites in both organisms. The mature mutarotase consists of 361 amino acids and has a calculated molecular weight of 38457 Da. Expression of mutarotase at a high level in a recombinant E. coli destabilizes the outer membrane. This results in coordinated leakage of mutarotase and beta-lactamase into the culture broth.

Acinetobacter↗
PubMed1993

Purification and characterization of homospermidine synthase in Acinetobacter tartarogenes ATCC 31105.

Homospermidine synthase, catalyzing the formation of homospermidine [H2N(CH2)4NH-(CH2)4NH2] from putrescine and NAD+ with concomitant liberation of NH3, was purified 600-fold over the crude extract with a yield of about 14% to homogeneity from Acinetobacter tartarogenes ATCC 31105. The enzyme had a native molecular mass of 102 kDa, with a pI of 5.0, and was apparently composed of two identical subunits (52 kDa), suggesting that a single protein catalyzes two serial reactions, oxidation of putrescine to 4-aminobutyraldehyde and subsequent reduction of the putative Schiff base formed between this aldehyde and a second molecule of putrescine to homospermidine. The Km values for putrescine and NAD+ were 280 and 18 microM, respectively. 1,3-Diaminopropane and cadaverine were inactive as substrates, and NAD+ could not be replaced by NADP+. 1,3-Diaminopropane and NADH were potent competitive inhibitors. The enzyme had a pH optimum of 8.7, was most active at 30 degrees C, and required K+ and dithiothreitol for full activity. Putrescine and NAD+ protected the enzyme from the inhibition by thiol reagents. The NH2-terminal amino acid sequence was AQWPVYGKISGPVVI. Some of these properties were compared with those of the homospermidine synthases from a photosynthetic bacterium, Rhodopseudomonas viridis and a plant, Lathyrus sativus.

Acinetobacter↗