Combating multidrug-resistant Gram-negative bacterial infections

Xu, Zhenghu; Flavin, Michael T.; Flavin, John

doi:10.1517/13543784.2014.848853

Cited by 113 publications

(91 citation statements)

References 122 publications

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“…The rise of multidrugresistant strains is especially problematic for Gram-negative pathogens due to the scarce or even inexistence of new active antibiotics, leading to serious life-threatening human infectious diseases (Xu et al 2014). Citrobacter spp.…”

Section: Discussionmentioning

confidence: 99%

Characterization and genome sequencing of a Citrobacter freundii phage CfP1 harboring a lysin active against multidrug-resistant isolates

Oliveira

Pinto

Oliveira

et al. 2016

Appl Microbiol Biotechnol

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Citrobacter spp., although frequently ignored, is emerging as an important nosocomial bacterium able to cause various superficial and systemic life-threatening infections. Considered to be hard-to-treat bacterium due to its pattern of high antibiotic resistance, it is important to develop effective measures for early and efficient therapy. In this study, the first myovirus (vB_CfrM_CfP1) lytic for Citrobacter freundii was microbiologically and genomically characterized. Its morphology, activity spectrum, burst size, and biophysical stability spectrum were determined. CfP1 specifically infects C. freundii, has broad host range (>85 %; 21 strains tested), a burst size of 45 PFU/cell, and is very stable under different temperatures (−20 to 50°C) and pH (3 to 11) values. CfP1 demonstrated to be highly virulent against multidrug-resistant clinical isolates up to 12 antibiotics, including penicillins, cephalosporins, carbapenems, and fluroquinoles. Genomically, CfP1 has a dsDNA molecule with 180,219 bp with average GC content of 43.1 % and codes for 273 CDSs. The genome architecture is organized into function-specific gene clusters typical for tailed phages, sharing 46 to 94 % nucleotide identity to other Citrobacter phages. The lysin gene encoding a predicted D-Ala-D-Ala carboxypeptidase was also cloned and expressed in Escherichia coli and its activity evaluated in terms of pH, ionic strength, and temperature. The lysine optimum activity was reached at 20 mM HEPES, pH 7 at 37°C, and was able to significantly reduce all C. freundii (>2 logs) as well as Citrobacter koseri (>4 logs) strains tested. Interestingly, the antimicrobial activity of this enzyme was performed without the need of pretreatment with outer membrane-destabilizing agents. These results indicate that CfP1 lysin is a good candidate to control problematic Citrobacter infections, for which current antibiotics are no longer effective.

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Section: Discussionmentioning

confidence: 99%

Characterization and genome sequencing of a Citrobacter freundii phage CfP1 harboring a lysin active against multidrug-resistant isolates

Oliveira

Pinto

Oliveira

et al. 2016

Appl Microbiol Biotechnol

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“…MDR bacteria [2]. Naturally, semi-synthetic drugs were made without choice to overcome the action of multi-drug resistant genes located in bacterial plasmids that inactivate the antibiotics by different mode of actions [10].…”

Section: Insights In Biomedicinementioning

confidence: 99%

“…Past 75 years are the golden era of drug development and few thousands penicillin drug derivatives are produced targeting bacterial cell wall peptidoglycan synthesis [1,2]. Dr. Selman A. Waksman discovered over twenty antibiotics from bacteria, actinomycetes and fungi including streptomycin and chloramphenicol that eradicated TB and typhoid in 1950s respectively [3].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of AMR: Bacteria Won the Battle Against Antibiotics

Ak¹

2017

Insights Biomed

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“…natural products pre-optimized by microorganisms) or for alternative strategies (e.g. active transport machineries of Gram-negative pathogens (Ji et al 2012;Górska et al 2014;Mislin and Schalk 2014) (Saha et al 2013;Wang et al 2014;Johnstone and Nolan 2015) (Page 2013;Górska et al 2014;Mislin and Schalk 2014;Xu et al 2014b;Zgurskaya et al 2015)) need to be intensified significantly. Table 1: Bacterial targets and approved antimicrobial compounds addressing them.…”

Section: Lessons Learned From Druggable Targets In Bacteriamentioning

confidence: 99%

“…; O Co ell et al ;Butle et al ;B o et al ;Xu et al 2014a;Bush 2015;Paris 2015). For this purpose, a brief overview of existing druggable targets and common features among them is given, followed by a review of promising novel scaffolds that address existing as well as novel targets.…”

Section: Introductionmentioning

confidence: 99%

New Structural Templates for Clinically Validated and Novel Targets in Antimicrobial Drug Research and Development

Klahn

Brönstrup

2016

Current Topics in Microbiology and Immunology

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Abstract:The development of bacterial resistance against current antibiotic drugs necessitates a continuous renewal of the arsenal of efficacious drugs. This imperative has not been met by the output of antibiotic research and development of the past decades for various reasons, including the declining efforts of large pharma companies in this area. Moreover, the majority of novel antibiotics are chemical derivatives of existing structures that represent mostly step innovations, implying that the available chemical space may be exhausted. This review negates this impression by showcasing recent achievements in lead finding and optimization of antibiotics that have novel or unexplored chemical structures. Not surprisingly, many of the novel structural templates like teixobactins, lysocin, griselimycin, or the albicidin/cystobactamid pair were discovered from natural sources. Additional compounds were obtained from the screening of synthetic libraries and chemical synthesis, including the gyrase-inhibiting NTBI s a d spiropyrimidinetrione, the tarocin and targocil inhibitors of wall teichoic acid synthesis, or the boronates and diazabicyclo[3.2

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Combating multidrug-resistant Gram-negative bacterial infections

Cited by 113 publications

References 122 publications

Characterization and genome sequencing of a Citrobacter freundii phage CfP1 harboring a lysin active against multidrug-resistant isolates

Characterization and genome sequencing of a Citrobacter freundii phage CfP1 harboring a lysin active against multidrug-resistant isolates

Mechanisms of AMR: Bacteria Won the Battle Against Antibiotics

New Structural Templates for Clinically Validated and Novel Targets in Antimicrobial Drug Research and Development

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