scholarly journals Effect of Subinhibitory Concentrations of Antibiotics and Disinfectants on ISAba-Mediated Inactivation of Lipooligosaccharide Biosynthesis Genes in Acinetobacter baumannii

Antibiotics ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1259
Author(s):  
Héctor Olmeda-López ◽  
Andrés Corral-Lugo ◽  
Michael J. McConnell
Keyword(s):  
Type Strain ◽  
Consensus Sequence ◽  
Insertion Site ◽  
Colistin Resistance ◽  
Insertional Inactivation ◽  
Insertion Elements ◽  
Insertion Sites ◽  
Subinhibitory Concentrations ◽  
High Level ◽  
Level Resistance

Inactivation of the lipooligosaccharide (LOS) biosynthesis genes lpxA, lpxC and lpxD by ISAba insertion elements results in high-level resistance to colistin in A. baumannii. In the present study, we quantify the rate of spontaneous insertional inactivation of LOS biosynthesis genes by ISAba elements in the ATCC 19606-type strain and two multidrug clinical isolates. Using insertional inactivation of lpxC by ISAba11 in the ATCC 19606 strain as a model, we determine the effect of several subinhibitory concentrations of the antibiotics, namely tetracycline, ciprofloxacin, meropenem, kanamycin and rifampicin, as well as the disinfectants ethanol and chlorhexidine on ISAba11 insertion frequencies. Notably, subinhibitory concentrations of tetracycline significantly increased ISAba11 insertion, and rifampicin completely inhibited the emergence of colistin resistance due to ISAba11 inactivation of lpxC. Sequencing of ISAba11 insertion sites within the lpxC gene demonstrated that insertions clustered between nucleotides 382 and 618 (58.3% of unique insertions detected), indicating that this may be a hotspot for ISAba11 insertion. The alignment of insertion sites revealed a semi-conserved AT-rich consensus sequence upstream of the ISAba11 insertion site, suggesting that ISAba11 insertion sites may be sequence-dependent. This study explores previously uncharacterized aspects regarding the acquisition of colistin resistance through insertional activation in LOS biosynthesis genes in A. baumannii.

scholarly journals Role of β-Lactamases and Porins in Resistance to Ertapenem and Other β-Lactams in Klebsiella pneumoniae

2004 ◽  
Vol 48 (8) ◽  
pp. 3203-3206 ◽  
Author(s):  
George A. Jacoby ◽  
Debra M. Mills ◽  
Nancy Chow
Keyword(s):  
Klebsiella Pneumoniae ◽  
Outer Membrane ◽  
Type Strain ◽  
Wild Type Strain ◽  
Outer Membrane Proteins ◽  
Wild Type ◽  
Resistant Mutants ◽  
High Level ◽  
Level Resistance

ABSTRACT High-level resistance to ertapenem was produced by β-lactamases of groups 1, 2f, and 3 in a strain of Klebsiella pneumoniae deficient in Omp35 and Omp36. From a wild-type strain producing ACT-1 β-lactamase, ertapenem-resistant mutants for which the ertapenem MICs were up to 128 μg/ml and expression of outer membrane proteins was diminished could be selected.

scholarly journals Postantibiotic effect of sanfetrinem compared with those of six other agents against 12 penicillin-susceptible and -resistant pneumococci.

1997 ◽  
Vol 41 (10) ◽  
pp. 2173-2176 ◽  
Author(s):  
S K Spangler ◽  
G Lin ◽  
M R Jacobs ◽  
P C Appelbaum
Keyword(s):  
Penicillin G ◽  
Postantibiotic Effect ◽  
Beta Lactams ◽  
The Mean ◽  
Subinhibitory Concentrations ◽  
High Level ◽  
Level Resistance

The postantibiotic effect (PAE) and postantibiotic sub-MIC effect (PAE-SME) of sanfetrinem were compared to those of penicillin G, amoxicillin, cefpodoxime, ceftriaxone, imipenem, and clarithromycin against four penicillin-susceptible, four intermediately susceptible, and four resistant pneumococci. The MICs of imipenem were the lowest against all of the strains (0.03 to 0.5 microg/ml), followed by those of sanfetrinem (0.016 to 1.0 microg/ml), amoxicillin and ceftriaxone (0.016 to 2.0 microg/ml), and cefpodoxime (0.03 to 8.0 microg/ml). High-level resistance to clarithromycin (MIC, >64.0 microg/ml) was seen in three selected strains. The PAEs of all of the oral beta-lactams tested were similar for all of the strains, ranging from 1 to 6.5 h. The PAEs of ceftriaxone and imipenem ranged from 1 to 8 h, and those of clarithromycin ranged from 1 to 7 h. The mean PAEs of all of the beta-lactams and clarithromycin were 2.8 to 4.3 and 2.5 h, respectively. PAE-SMEs could not be determined for all of the strains due to complete killing, especially at high subinhibitory concentrations. However, the overall pattern with all of the compounds tested was that PAE-SMEs were longer than PAEs. Measurable PAE-SMEs of sanfetrinem at the three subinhibitory concentrations (0.125, 0.25, and 0.5 times the MIC) were 2 to 7, 2 to 7, and 3 to 6 h, while those of amoxicillin and cefpodoxime were 1 to 7.5, 2 to 4, and 4 to 9 and 2 to 7, 4 to 7, and 4 to 6 h, respectively. Measurable PAE-SMEs of ceftriaxone and imipenem were 1 to 6.5, 2 to 9, and 2 to 9 and 1.5 to 6, 2 to 5.8, and 4 to 7.7 h, respectively. Measurable clarithromycin PAE-SMEs were 1 to 5, 1 to 5, and 1 to 6 h at the three concentrations.

scholarly journals Absence of mgrB Alleviates Negative Growth Effects of Colistin Resistance in Enterobacter cloacae

Antibiotics ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 825
Author(s):  
Jessie E. Wozniak ◽  
Aroon T. Chande ◽  
Eileen M. Burd ◽  
Victor I. Band ◽  
Sarah W. Satola ◽  
...  
Keyword(s):  
Enterobacter Cloacae ◽  
Clinical Isolates ◽  
Growth Defect ◽  
Colistin Resistance ◽  
Significant Growth ◽  
Growth Effects ◽  
Growth Defects ◽  
High Level ◽  
Negative Growth ◽  
Level Resistance

Colistin is an important last-line antibiotic to treat highly resistant Enterobacter infections. Resistance to colistin has emerged among clinical isolates but has been associated with a significant growth defect. Here, we describe a clinical Enterobacter isolate with a deletion of mgrB, a regulator of colistin resistance, leading to high-level resistance in the absence of a growth defect. The identification of a path to resistance unrestrained by growth defects suggests colistin resistance could become more common in Enterobacter.

scholarly journals Construction of an Enterococcus faecalis Tn917-Mediated-Gene-Disruption Library Offers Insight into Tn917 Insertion Patterns

2004 ◽  
Vol 186 (21) ◽  
pp. 7280-7289 ◽  
Author(s):  
Danielle A. Garsin ◽  
Jonathan Urbach ◽  
Jose C. Huguet-Tapia ◽  
Joseph E. Peters ◽  
Frederick M. Ausubel
Keyword(s):  
Enterococcus Faecalis ◽  
Hot Spot ◽  
Consensus Sequence ◽  
Insertion Site ◽  
Open Reading Frames ◽  
Site Preference ◽  
Specific Sequence ◽  
The Public ◽  
Insertion Sites ◽  
Replication Terminus

ABSTRACT Sequencing the insertion sites of 8,865 Tn917 insertions in Enterococcus faecalis strain OG1RF identified a hot spot in the replication terminus region corresponding to 6% of the genome where 65% of the transposons had inserted. In E. faecalis, Tn917 preferentially inserted at a 29-bp consensus sequence centered on TATAA, a 5-bp sequence that is duplicated during insertion. The regional insertion site preference at the chromosome terminus was not observed in another low-G+C gram-positive bacterium, Listeria monocytogenes, although the consensus insertion sequence was the same. The 8,865 Tn917 insertion sites sequenced in E. faecalis corresponded to only ∼610 different open reading frames, far fewer than the predicted number of 2,400, assuming random insertion. There was no significant preference in orientation of the Tn917 insertions with either transcription or replication. Even though OG1RF has a smaller genome than strain V583 (2.8 Mb versus 3.2 Mb), the only E. faecalis strain whose sequence is in the public domain, over 10% of the Tn917 insertions appear to be in a OG1RF-specific sequence, suggesting that there are significant genomic differences among E. faecalis strains.

The Chemistry of Drugs to Treat Candida albicans

2019 ◽  
Vol 19 (28) ◽  
pp. 2554-2566 ◽  
Author(s):  
Aurelio Ortiz ◽  
Estibaliz Sansinenea
Keyword(s):  
Candida Species ◽  
Antifungal Drugs ◽  
New Drugs ◽  
Drug Classes ◽  
Life Threatening ◽  
Antifungal Substances ◽  
High Level ◽  
Systemic Infections ◽  
New Compounds ◽  
Level Resistance

Background:: Candida species are in various parts of the human body as commensals. However, they can cause local mucosal infections and, sometimes, systemic infections in which Candida species can spread to all major organs and colonize them. Objective:: For the effective treatment of the mucosal infections and systemic life-threatening fungal diseases, a considerably large number of antifungal drugs have been developed and used for clinical purposes that comprise agents from four main drug classes: the polyenes, azoles, echinocandins, and antimetabolites. Method: : The synthesis of some of these drugs is available, allowing synthetic modification of the molecules to improve the biological activity against Candida species. The synthetic methodology for each compound is reviewed. Results: : The use of these compounds has caused a high-level resistance against these drugs, and therefore, new antifungal substances have been described in the last years. The organic synthesis of the known and new compounds is reported. Conclusion: : This article summarizes the chemistry of the existing agents, both the old drugs and new drugs, in the treatment of infections due to C. albicans, including the synthesis of the existing drugs.

scholarly journals Mutations in fbiD (Rv2983) as a Novel Determinant of Resistance to Pretomanid and Delamanid in Mycobacterium tuberculosis

2020 ◽  
Vol 65 (1) ◽  
pp. e01948-20
Author(s):  
Dalin Rifat ◽  
Si-Yang Li ◽  
Thomas Ioerger ◽  
Keshav Shah ◽  
Jean-Philippe Lanoix ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Clinical Evidence ◽  
Clinical Samples ◽  
Loss Of Function ◽  
Wild Type ◽  
Content Type ◽  
Solid Media ◽  
High Level ◽  
Level Resistance

ABSTRACTThe nitroimidazole prodrugs delamanid and pretomanid comprise one of only two new antimicrobial classes approved to treat tuberculosis (TB) in 50 years. Prior in vitro studies suggest a relatively low barrier to nitroimidazole resistance in Mycobacterium tuberculosis, but clinical evidence is limited to date. We selected pretomanid-resistant M. tuberculosis mutants in two mouse models of TB using a range of pretomanid doses. The frequency of spontaneous resistance was approximately 10−5 CFU. Whole-genome sequencing of 161 resistant isolates from 47 mice revealed 99 unique mutations, of which 91% occurred in 1 of 5 genes previously associated with nitroimidazole activation and resistance, namely, fbiC (56%), fbiA (15%), ddn (12%), fgd (4%), and fbiB (4%). Nearly all mutations were unique to a single mouse and not previously identified. The remaining 9% of resistant mutants harbored mutations in Rv2983 (fbiD), a gene not previously associated with nitroimidazole resistance but recently shown to be a guanylyltransferase necessary for cofactor F420 synthesis. Most mutants exhibited high-level resistance to pretomanid and delamanid, although Rv2983 and fbiB mutants exhibited high-level pretomanid resistance but relatively small changes in delamanid susceptibility. Complementing an Rv2983 mutant with wild-type Rv2983 restored susceptibility to pretomanid and delamanid. By quantifying intracellular F420 and its precursor Fo in overexpressing and loss-of-function mutants, we provide further evidence that Rv2983 is necessary for F420 biosynthesis. Finally, Rv2983 mutants and other F420H2-deficient mutants displayed hypersusceptibility to some antibiotics and to concentrations of malachite green found in solid media used to isolate and propagate mycobacteria from clinical samples.

scholarly journals Molecular pathways to high-level azithromycin resistance in Neisseria gonorrhoeae

2021 ◽  
Author(s):  
J G E Laumen ◽  
S S Manoharan-Basil ◽  
E Verhoeven ◽  
S Abdellati ◽  
I De Baetselier ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Ribosomal Proteins ◽  
Efflux Pump ◽  
23S Rrna ◽  
Rrna Gene ◽  
23S Rrna Gene ◽  
Evolution Of Resistance ◽  
High Level ◽  
Azithromycin Resistance ◽  
Level Resistance

Abstract Background The prevalence of azithromycin resistance in Neisseria gonorrhoeae is increasing in numerous populations worldwide. Objectives To characterize the genetic pathways leading to high-level azithromycin resistance. Methods A customized morbidostat was used to subject two N. gonorrhoeae reference strains (WHO-F and WHO-X) to dynamically sustained azithromycin pressure. We tracked stepwise evolution of resistance by whole genome sequencing. Results Within 26 days, all cultures evolved high-level azithromycin resistance. Typically, the first step towards resistance was found in transitory mutations in genes rplD, rplV and rpmH (encoding the ribosomal proteins L4, L22 and L34 respectively), followed by mutations in the MtrCDE-encoded efflux pump and the 23S rRNA gene. Low- to high-level resistance was associated with mutations in the ribosomal proteins and MtrCDE efflux pump. However, high-level resistance was consistently associated with mutations in the 23S ribosomal RNA, mainly the well-known A2059G and C2611T mutations, but also at position A2058G. Conclusions This study enabled us to track previously reported mutations and identify novel mutations in ribosomal proteins (L4, L22 and L34) that may play a role in the genesis of azithromycin resistance in N. gonorrhoeae.

scholarly journals WGS of Commensal Neisseria Reveals Acquisition of a New Ribosomal Protection Protein (MsrD) as a Possible Explanation for High Level Azithromycin Resistance in Belgium

Pathogens ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 384
Author(s):  
Tessa de Block ◽  
Jolein Gyonne Elise Laumen ◽  
Christophe Van Dijck ◽  
Said Abdellati ◽  
Irith De Baetselier ◽  
...  
Keyword(s):  
Integration Site ◽  
Bacterial Species ◽  
Resistance Mechanism ◽  
Health Concern ◽  
Sex With Men ◽  
High Level ◽  
Ribosomal Protection Protein ◽  
Commensal Neisseria ◽  
Level Resistance ◽  
Ribosomal Protection

In this study, we characterized all oropharyngeal and anorectal isolates of Neisseria spp. in a cohort of men who have sex with men. This resulted in a panel of pathogenic Neisseria (N. gonorrhoeae [n = 5] and N. meningitidis [n = 5]) and nonpathogenic Neisseria (N. subflava [n = 11], N. mucosa [n = 3] and N. oralis [n = 2]). A high proportion of strains in this panel were resistant to azithromycin (18/26) and ceftriaxone (3/26). Whole genome sequencing (WGS) of these strains identified numerous mutations that are known to confer reduced susceptibility to azithromycin and ceftriaxone in N. gonorrhoeae. The presence or absence of these known mutations did not explain the high level resistance to azithromycin (>256 mg/L) in the nonpathogenic isolates (8/16). After screening for antimicrobial resistance (AMR) genes, we found a ribosomal protection protein, Msr(D), in these highly azithromycin resistant nonpathogenic strains. The complete integration site originated from Streptococcus pneumoniae and is associated with high level resistance to azithromycin in many other bacterial species. This novel AMR resistance mechanism to azithromycin in nonpathogenic Neisseria could be a public health concern if it were to be transmitted to pathogenic Neisseria. This study demonstrates the utility of WGS-based surveillance of nonpathogenic Neisseria.

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