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Antibiotics, Volume 5, Issue 4 (December 2016)

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Research

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Open AccessArticle The Novel Aminomethylcycline Omadacycline Has High Specificity for the Primary Tetracycline-Binding Site on the Bacterial Ribosome
Antibiotics 2016, 5(4), 32; doi:10.3390/antibiotics5040032
Received: 27 March 2016 / Revised: 1 September 2016 / Accepted: 12 September 2016 / Published: 22 September 2016
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Abstract
Omadacycline is an aminomethylcycline antibiotic with potent activity against many Gram-positive and Gram-negative pathogens, including strains carrying the major efflux and ribosome protection resistance determinants. This makes it a promising candidate for therapy of severe infectious diseases. Omadacycline inhibits bacterial protein biosynthesis and
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Omadacycline is an aminomethylcycline antibiotic with potent activity against many Gram-positive and Gram-negative pathogens, including strains carrying the major efflux and ribosome protection resistance determinants. This makes it a promising candidate for therapy of severe infectious diseases. Omadacycline inhibits bacterial protein biosynthesis and competes with tetracycline for binding to the ribosome. Its interactions with the 70S ribosome were, therefore, analyzed in great detail and compared with tigecycline and tetracycline. All three antibiotics are inhibited by mutations in the 16S rRNA that mediate resistance to tetracycline in Brachyspira hyodysenteriae, Helicobacter pylori, Mycoplasma hominis, and Propionibacterium acnes. Chemical probing with dimethyl sulfate and Fenton cleavage with iron(II)-complexes of the tetracycline derivatives revealed that each antibiotic interacts in an idiosyncratic manner with the ribosome. X-ray crystallography had previously revealed one primary binding site for tetracycline on the ribosome and up to five secondary sites. All tetracyclines analyzed here interact with the primary site and tetracycline also with two secondary sites. In addition, each derivative displays a unique set of non-specific interactions with the 16S rRNA. Full article
(This article belongs to the Special Issue Inhibitors of the Translational Apparatus)
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Open AccessArticle The Peptidoglycan Pattern of Staphylococcus carnosus TM300—Detailed Analysis and Variations Due to Genetic and Metabolic Influences
Antibiotics 2016, 5(4), 33; doi:10.3390/antibiotics5040033
Received: 7 July 2016 / Revised: 9 August 2016 / Accepted: 2 September 2016 / Published: 23 September 2016
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Abstract
The Gram-positive bacterium Staphylococcus carnosus (S. carnosus) TM300 is an apathogenic staphylococcal species commonly used in meat starter cultures. As with all Gram-positive bacteria, its cytoplasmic membrane is surrounded by a thick peptidoglycan (PGN) or murein sacculus consisting of several layers
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The Gram-positive bacterium Staphylococcus carnosus (S. carnosus) TM300 is an apathogenic staphylococcal species commonly used in meat starter cultures. As with all Gram-positive bacteria, its cytoplasmic membrane is surrounded by a thick peptidoglycan (PGN) or murein sacculus consisting of several layers of glycan strands cross-linked by peptides. In contrast to pathogenic staphylococci, mainly Staphylococcus aureus (S. aureus), the chemical composition of S. carnosus PGN is not well studied so far. UPLC/MS analysis of enzymatically digested S. carnosus TM300 PGN revealed substantial differences in its composition compared to the known pattern of S. aureus. While in S. aureus the uncross-linked stem peptide consists of a pentapeptide, in S. carnosus, this part of the PGN is shortened to tripeptides. Furthermore, we found the PGN composition to vary when cells were incubated under certain conditions. The collective overproduction of HlyD, FtsE and FtsX—a putative protein complex interacting with penicillin-binding protein 2 (PBP2)—caused the reappearance of classical penta stem peptides. In addition, under high sugar conditions, tetra stem peptides occur due to overflow metabolism. This indicates that S. carnosus TM300 cells adapt to various conditions by modification of their PGN. Full article
(This article belongs to the Special Issue Bacterial Cell Wall as Antimicrobial Target)
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Open AccessCommunication Discrepancy in Vancomycin AUC/MIC Ratio Targeted Attainment Based upon the Susceptibility Testing in Staphylococcus aureus
Antibiotics 2016, 5(4), 34; doi:10.3390/antibiotics5040034
Received: 27 June 2016 / Revised: 15 September 2016 / Accepted: 20 September 2016 / Published: 27 September 2016
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Abstract
This study demonstrated a statistically significant difference in vancomycin minimum inhibitory concentration (MIC) for Staphylococcus aureus between a common automated system (Vitek 2) and the E-test method in patients with S. aureus bloodstream infections. At an area under the serum concentration time curve
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This study demonstrated a statistically significant difference in vancomycin minimum inhibitory concentration (MIC) for Staphylococcus aureus between a common automated system (Vitek 2) and the E-test method in patients with S. aureus bloodstream infections. At an area under the serum concentration time curve (AUC) threshold of 400 mg∙h/L, we would have reached the current Infectious Diseases Society of America (IDSA)/American Society of Health System Pharmacists (ASHP)/Society of Infectious Diseases Pharmacists (SIDP) guideline suggested AUC/MIC target in almost 100% of patients while using the Vitek 2 MIC data; however, we could only generate 40% target attainment while using E-test MIC data (p < 0.0001). An AUC of 450 mg∙h/L or greater was required to achieve 100% target attainment using either Vitek 2 or E-test MIC results. Full article
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Open AccessArticle Pectocin M1 (PcaM1) Inhibits Escherichia coli Cell Growth and Peptidoglycan Biosynthesis through Periplasmic Expression
Antibiotics 2016, 5(4), 36; doi:10.3390/antibiotics5040036
Received: 18 July 2016 / Revised: 14 September 2016 / Accepted: 23 September 2016 / Published: 8 October 2016
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Abstract
Colicins are bacterial toxins produced by some Escherichia coli strains. They exhibit either enzymatic or pore-forming activity towards a very limited number of bacterial species, due to the high specificity of their reception and translocation systems. Yet, we succeeded in making the colicin
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Colicins are bacterial toxins produced by some Escherichia coli strains. They exhibit either enzymatic or pore-forming activity towards a very limited number of bacterial species, due to the high specificity of their reception and translocation systems. Yet, we succeeded in making the colicin M homologue from Pectobacterium carotovorum, pectocin M1 (PcaM1), capable of inhibiting E. coli cell growth by bypassing these reception and translocation steps. This goal was achieved through periplasmic expression of this pectocin. Indeed, when appropriately addressed to the periplasm of E. coli, this pectocin could exert its deleterious effects, i.e., the enzymatic degradation of the peptidoglycan lipid II precursor, which resulted in the arrest of the biosynthesis of this essential cell wall polymer, dramatic morphological changes and, ultimately, cell lysis. This result leads to the conclusion that colicin M and its various orthologues constitute powerful antibacterial molecules able to kill any kind of bacterium, once they can reach their lipid II target. They thus have to be seriously considered as promising alternatives to antibiotics. Full article
(This article belongs to the Special Issue Bacterial Cell Wall as Antimicrobial Target)
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Open AccessArticle Conformational Response of 30S-bound IF3 to A-Site Binders Streptomycin and Kanamycin
Antibiotics 2016, 5(4), 38; doi:10.3390/antibiotics5040038
Received: 20 April 2016 / Revised: 22 October 2016 / Accepted: 6 December 2016 / Published: 13 December 2016
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Abstract
Aminoglycoside antibiotics are widely used to treat infectious diseases. Among them, streptomycin and kanamycin (and derivatives) are of importance to battle multidrug-resistant (MDR) Mycobacterium tuberculosis. Both drugs bind the small ribosomal subunit (30S) and inhibit protein synthesis. Genetic, structural, and biochemical studies
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Aminoglycoside antibiotics are widely used to treat infectious diseases. Among them, streptomycin and kanamycin (and derivatives) are of importance to battle multidrug-resistant (MDR) Mycobacterium tuberculosis. Both drugs bind the small ribosomal subunit (30S) and inhibit protein synthesis. Genetic, structural, and biochemical studies indicate that local and long-range conformational rearrangements of the 30S subunit account for this inhibition. Here, we use intramolecular FRET between the C- and N-terminus domains of the flexible IF3 to monitor real-time perturbations of their binding sites on the 30S platform. Steady and pre-steady state binding experiments show that both aminoglycosides bring IF3 domains apart, promoting an elongated state of the factor. Binding of Initiation Factor IF1 triggers closure of IF3 bound to the 30S complex, while both aminoglycosides revert the IF1-dependent conformation. Our results uncover dynamic perturbations across the 30S subunit, from the A-site to the platform, and suggest that both aminoglycosides could interfere with prokaryotic translation initiation by modulating the interaction between IF3 domains with the 30S platform. Full article
(This article belongs to the Special Issue Inhibitors of the Translational Apparatus)
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Open AccessArticle Quorum Sensing and the Use of Quorum Quenchers as Natural Biocides to Inhibit Sulfate-Reducing Bacteria
Antibiotics 2016, 5(4), 39; doi:10.3390/antibiotics5040039
Received: 6 October 2016 / Revised: 23 November 2016 / Accepted: 6 December 2016 / Published: 15 December 2016
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Abstract
Sulfate-reducing bacteria (SRB) are one of the main protagonist groups of biocorrosion in the seawater environment. Given their principal role in biocorrosion, it remains a crucial task to develop strategies to reduce the abundance of SRBs. Conventional approaches include the use of biocides
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Sulfate-reducing bacteria (SRB) are one of the main protagonist groups of biocorrosion in the seawater environment. Given their principal role in biocorrosion, it remains a crucial task to develop strategies to reduce the abundance of SRBs. Conventional approaches include the use of biocides and antibiotics, which can impose health, safety, and environmental concerns. This review examines an alternative approach to this problem. This is achieved by reviewing the role of quorum sensing (QS) in SRB populations and its impact on the biofilm formation process. Genome databases of SRBs are mined to look for putative QS systems and homologous protein sequences representative of autoinducer receptors or synthases. Subsequently, this review puts forward the potential use of quorum quenchers as natural biocides against SRBs and outlines the potential strategies for the implementation of this approach. Full article

Review

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Open AccessReview Resistance to β-Lactams in Neisseria ssp Due to Chromosomally Encoded Penicillin-Binding Proteins
Antibiotics 2016, 5(4), 35; doi:10.3390/antibiotics5040035
Received: 20 July 2016 / Revised: 22 September 2016 / Accepted: 23 September 2016 / Published: 28 September 2016
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Abstract
Neisseria meningitidis and Neisseria gonorrhoeae are human pathogens that cause a variety of life-threatening systemic and local infections, such as meningitis or gonorrhoea. The treatment of such infection is becoming more difficult due to antibiotic resistance. The focus of this review is on
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Neisseria meningitidis and Neisseria gonorrhoeae are human pathogens that cause a variety of life-threatening systemic and local infections, such as meningitis or gonorrhoea. The treatment of such infection is becoming more difficult due to antibiotic resistance. The focus of this review is on the mechanism of reduced susceptibility to penicillin and other β-lactams due to the modification of chromosomally encoded penicillin-binding proteins (PBP), in particular PBP2 encoded by the penA gene. The variety of penA alleles and resulting variant PBP2 enzymes is described and the important amino acid substitutions are presented and discussed in a structural context. Full article
(This article belongs to the Special Issue Bacterial Cell Wall as Antimicrobial Target)
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Open AccessReview Antimicrobial Usage and Antimicrobial Resistance in Animal Production in Southeast Asia: A Review
Antibiotics 2016, 5(4), 37; doi:10.3390/antibiotics5040037
Received: 9 September 2016 / Revised: 19 October 2016 / Accepted: 20 October 2016 / Published: 2 November 2016
Cited by 1 | PDF Full-text (1206 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Southeast Asia is an area of great economic dynamism. In recent years, it has experienced a rapid rise in the levels of animal product production and consumption. The region is considered to be a hotspot for infectious diseases and antimicrobial resistance (AMR). We
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Southeast Asia is an area of great economic dynamism. In recent years, it has experienced a rapid rise in the levels of animal product production and consumption. The region is considered to be a hotspot for infectious diseases and antimicrobial resistance (AMR). We reviewed English-language peer-reviewed publications related to antimicrobial usage (AMU) and AMR in animal production, as well as antimicrobial residues in meat and fish from 2000 to 2016, in the region. There is a paucity of data from most countries and for most bacterial pathogens. Most of the published work relates to non-typhoidal Salmonella (NTS), Escherichia coli (E. coli), and Campylobacter spp. (mainly from Vietnam and Thailand), Enterococcus spp. (Malaysia), and methicillin-resistant Staphylococcus aureus (MRSA) (Thailand). However, most studies used the disk diffusion method for antimicrobial susceptibility testing; breakpoints were interpreted using Clinical Standard Laboratory Institute (CSLI) guidelines. Statistical models integrating data from publications on AMR in NTS and E. coli studies show a higher overall prevalence of AMR in pig isolates, and an increase in levels of AMR over the years. AMU studies (mostly from Vietnam) indicate very high usage levels of most types of antimicrobials, including beta-lactams, aminoglycosides, macrolides, and quinolones. This review summarizes information about genetic determinants of resistance, most of which are transferrable (mostly plasmids and integrons). The data in this review provide a benchmark to help focus research and policies on AMU and AMR in the region. Full article
(This article belongs to the Special Issue Antibiotics in Animal Health)
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