Insertion Sequence IS
            <i>Aba11</i>
            Is Involved in Colistin Resistance and Loss of Lipopolysaccharide in Acinetobacter baumannii

Moffatt, Jennifer H.; Harper, Marina; Adler, Ben; Nation, Roger L.; Li, Jian; Boyce, John D.

doi:10.1128/aac.01732-10

Cited by 172 publications

(156 citation statements)

References 11 publications

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“…Mutations in the pmrCAB operon, leading to increased production of the PmrAB system and modification of lipid A, have been identified in isolates of polymyxin-resistant A. baumannii (26,27). In addition, absence of lipid A in the cellular membrane, due to alterations in the lpx operon, has been found in laboratoryderived and clinical isolates of polymyxin-resistant A. baumannii (28,29). Corresponding findings have also been obtained for members of the Enterobacteriaceae.…”

Section: Discussionsupporting

confidence: 53%

Irreproducible and Uninterpretable Polymyxin B MICs for Enterobacter cloacae and Enterobacter aerogenes

2013

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Carbapenem-resistant Enterobacter species are emerging nosocomial pathogens. As with most multidrug-resistant Gram-negative pathogens, the polymyxins are often the only therapeutic option. In this study involving clinical isolates of E. cloacae and E. aerogenes, susceptibility testing methods with polymyxin B were analyzed. All isolates underwent testing by the broth microdilution (in duplicate) and agar dilution (in duplicate) methods, and select isolates were examined by the Etest method. Selected isolates were also examined for heteroresistance by population analysis profiling. Using a susceptibility breakpoint of <2 g/ml, categorical agreement by all four dilution tests (two broth microdilution and two agar dilution) was achieved in only 76/114 (67%) of E. cloacae isolates (65 susceptible, 11 resistant). Thirty-eight (33%) had either conflicting or uninterpretable results (multiple skip wells, i.e., wells that exhibit no growth although growth does occur at higher concentrations). Of the 11 consistently resistant isolates, five had susceptible MICs as determined by Etest. Heteroresistant subpopulations were detected in eight of eight isolates tested, with greater percentages in isolates with uninterpretable MICs. For E. aerogenes, categorical agreement between the four dilution tests was obtained in 48/56 (86%), with conflicting and/or uninterpretable results in 8/56 (14%). For polymyxin susceptibility testing of Enterobacter species, close attention must be paid to the presence of multiple skip wells, leading to uninterpretable results. Susceptibility also should not be assumed based on the results of a single test. Until the clinical relevance of skip wells is defined, interpretation of polymyxin susceptibility tests for Enterobacter species should be undertaken with extreme caution.

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Section: Discussionsupporting

confidence: 53%

Irreproducible and Uninterpretable Polymyxin B MICs for Enterobacter cloacae and Enterobacter aerogenes

2013

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“…Alterations in the lipid A biosynthesis genes (lpxA, lpxC, and lpxD) by amino acid substitutions, deletions, or insertion of ISAba1 are responsible for the loss of LPS [49,50]. A recent metabolomic study revealed that an LPS-deficient, colistin-resistant A. baumannii strain showed perturbation in specific amino acid and carbohydrate metabolites, particularly pentose phosphate pathway and TCA (tricarboxylic acid) cycle intermediates [37].…”

Section: Colistin Resistancementioning

confidence: 99%

Old drug, new findings: colistin resistance and dependence of Acinetobacter baumannii

Choi

Lee

2017

Precis Future Med

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Colistin is an old drug, and its use has recently resurged because of increasing antibiotic resistance in gram-negative bacteria such as Acinetobacter baumannii. Although the colistin resistance rates in gram-negative bacteria are currently not high, many colistin-resistant isolates are being identified and the possibility of horizontal transmission of colistin resistance has increased because of the plasmid-borne colistin resistance gene mcr-1 (mobilized colistin resistance). In this review, we have discussed colistin resistance in A. baumannii. In addition, we have reviewed an abnormal phenomenon called colistin dependence in A. baumannii.

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“…Alteration of the charge status of LPS, for example, by 4-amino-4-deoxy-L-arabinose modification, is one well-studied mechanism of resistance (21). More recently, it was discovered that resistance to colistin in A. baumannii ATCC 19606 could be mediated by the complete loss of LPS, in turn revealing that LPS is not essential in this organism, at least under typical in vitro growth conditions (22)(23)(24). This observation extended data from previous reports that LPS is not essential in certain other Gram-negative organisms (25)(26)(27).…”

mentioning

confidence: 99%

Characterization of an Acinetobacter baumannii lptD Deletion Strain: Permeability Defects and Response to Inhibition of Lipopolysaccharide and Fatty Acid Biosynthesis

et al. 2016

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Lipid A on the Gram-negative outer membrane (OM) is synthesized in the cytoplasm by the Lpx pathway and translocated to the OM by the Lpt pathway. Some Acinetobacter baumannii strains can tolerate the complete loss of lipopolysaccharide (LPS) resulting from the inactivation of early LPS pathway genes such as lpxC. Here, we characterized a mutant deleted for lptD, which encodes an OM protein that mediates the final translocation of fully synthesized LPS to the OM. Cells lacking lptD had a growth defect comparable to that of an lpxC deletion mutant under the growth conditions tested but were more sensitive to hydrophobic antibiotics, revealing a more significant impact on cell permeability from impaired LPS translocation than from the loss of LPS synthesis. Consistent with this, ATP leakage and N-phenyl-1-naphthylamine (NPN) fluorescence assays indicated a more severe impact of lptD deletion than of lpxC deletion on inner and outer membrane permeability, respectively. Targeted In most Gram-negative bacteria, many of the proteins responsible for lipopolysaccharide (LPS) synthesis and transport are essential, making them potential targets for antibacterial drug development. In particular, the nine conserved Lpx enzymes are considered promising for the development of novel antibiotics, since (3-deoxy-D-manno-oct-2-ulosonic acid) 2 -lipid A (Kdo 2 -lipid A) is the minimal LPS structure that supports a functional outer membrane (OM) and cell viability for most Gram-negative bacteria (1, 2). Indeed, the optimization of LpxC inhibitors has been an ongoing effort in antimicrobial research for over 2 decades, which has yielded compounds with impressive antibacterial activity against Gram-negative organisms such as Pseudomonas aeruginosa (1,(3)(4)(5)(6)(7)(8)(9). The identification of RJPXD33, an antimicrobial peptide that inhibits both Escherichia coli LpxA and LpxD, and a recently identified LpxH inhibitor suggests that other LPS biosynthetic steps could also be successfully targeted (10-12). POL7001, a peptidomimetic antibiotic that inhibits LptD, the final essential step of the LPS transport (Lpt) system, has potent and specific antibacterial activity against P. aeruginosa, which, importantly, indicates that the LPS transport and OM assembly machinery may be attractive targets for antibacterial discovery (13)(14)(15).Acinetobacter baumannii is an emerging opportunistic bacterial pathogen of increasing concern due to multidrug resistance (16). A. baumannii is noted for its ability to develop resistance against most conventional antibiotics through mechanisms such as the upregulation of efflux pumps and horizontal transfer of resistance genes (17)(18)(19). Because of this, clinical resistance is becoming a serious issue for this organism (as well as for other Gram-negative pathogens), often necessitating the use of antibiotics of last resort, such as polymyxins (19,20). Understanding resistance to polymyxins, which are cationic and utilize LPS to gain access to cells, has therefore become a focus of renewed in-

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Insertion Sequence IS Aba11 Is Involved in Colistin Resistance and Loss of Lipopolysaccharide in Acinetobacter baumannii

Cited by 172 publications

References 11 publications

Irreproducible and Uninterpretable Polymyxin B MICs for Enterobacter cloacae and Enterobacter aerogenes

Irreproducible and Uninterpretable Polymyxin B MICs for Enterobacter cloacae and Enterobacter aerogenes

Old drug, new findings: colistin resistance and dependence of Acinetobacter baumannii

Characterization of an Acinetobacter baumannii lptD Deletion Strain: Permeability Defects and Response to Inhibition of Lipopolysaccharide and Fatty Acid Biosynthesis

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