Oxidative Stress Induced by Polymyxin E Is Involved in Rapid Killing of<i>Paenibacillus polymyxa</i>

Yu, Zhiliang; Zhu, Yuyi; Qin, Wangrong; Yin, Jianhua; Qiu, Juanping

doi:10.1155/2017/5437139

Cited by 23 publications

(22 citation statements)

References 40 publications

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“…Accumulating evidence suggests that the hydroxyl radical death pathway could be activated as a downstream event of colistin exposure [ 88 , 89 ]. The fact that MCR-3 can modify lipid A moieties of LPS on bacterial membrane, an initial target of colistin, allowed us to hypothesize that expression of MCR-3 might physiologically prevent colistin-induced ROS production.…”

Section: Methodsmentioning

confidence: 99%

Spread of MCR-3 Colistin Resistance in China: An Epidemiological, Genomic and Mechanistic Study

Zhong

Srinivas

et al. 2018

EBioMedicine

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BackgroundMobilized resistance to colistin is evolving rapidly and its global dissemination poses a severe threat to human health and safety. Transferable colistin resistance gene, mcr-3, first identified in Shandong, China, has already been found in several countries in multidrug-resistant human infections. Here we track the spread of mcr-3 within 13 provinces in China and provide a complete characterization of its evolution, structure and function.MethodsA total of 6497 non-duplicate samples were collected from thirteen provinces in China, from 2016 to 2017 and then screened for the presence of mcr-3 gene by PCR amplification. mcr-3-positive isolates were analyzed for antibiotic resistance and by southern blot hybridization, transfer analysis and plasmid typing. We then examined the molecular evolution of MCR-3 through phylogenetic analysis. Furthermore, we also characterized the structure and function of MCR-3 through circular dichroism analyses, inductively coupled plasma mass spectrometry (ICP-MS), liquid chromatography mass spectrometry (LC/MS), confocal microscopy and chemical rescue tests.Findings49 samples (49/6497 = 0.75%) were mcr-3 positive, comprising 40 samples (40/4144 = 0.97%) from 2017 and 9 samples (9/2353 = 0.38%) from 2016. Overall, mcr-3-positive isolates were distributed in animals and humans in 8 of the 13 provinces. Three mcr-3-positive IncP-type and one mcr-1-bearing IncHI2-like plasmids were identified and characterized. MCR-3 clusters with PEA transferases from Aeromonas and other bacteria and forms a phylogenetic entity that is distinct from the MCR-1/2/P(M) family, the largest group of transferable colistin resistance determinants. Despite that the two domains of MCR-3 not being exchangeable with their counterparts in MCR-1/2, structure-guided functional mapping of MCR-3 defines a conserved PE-lipid recognizing cavity prerequisite for its enzymatic catalysis and its resultant phenotypic resistance to colistin. We therefore propose that MCR-3 uses a possible “ping-pong” mechanism to transfer the moiety of PEA from its donor PE to the 1(or 4′)-phosphate of lipid A via an adduct of MCR-3-bound PEA. Additionally, the expression of MCR-3 in E. coli prevents the colistin-triggered formation of reactive oxygen species (ROS) and interferes bacterial growth and viability.InterpretationOur results provide an evolutionary, structural and functional definition of MCR-3 and its epidemiology in China, paving the way for smarter policies, better surveillance and effective treatments.

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Section: Methodsmentioning

confidence: 99%

Spread of MCR-3 Colistin Resistance in China: An Epidemiological, Genomic and Mechanistic Study

Zhong

Srinivas

et al. 2018

EBioMedicine

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“…Paenibacillus polymyxa is a multifunctional Gram-positive (G + ) bacterium that has been reported to have applications in agriculture ( Hao and Chen, 2017 ), medicine ( Galea et al, 2017 ; Yu et al, 2017 ), and industry ( Lal and Tabacchioni, 2009 ). P. polymyxa has been in the list of substances reported under the Toxic Substance Control Act (TSCA) by the United States Environmental Protection Agency (EPA) 1 .…”

Section: Introductionmentioning

confidence: 99%

Complete Genome Sequence of Industrial Biocontrol Strain Paenibacillus polymyxa HY96-2 and Further Analysis of Its Biocontrol Mechanism

Luo

Cheng

et al. 2018

Front. Microbiol.

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Paenibacillus polymyxa (formerly known as Bacillus polymyxa) has been extensively studied for agricultural applications as a plant-growth-promoting rhizobacterium and is also an important biocontrol agent. Our team has developed the P. polymyxa strain HY96-2 from the tomato rhizosphere as the first microbial biopesticide based on P. polymyxa for controlling plant diseases around the world, leading to the commercialization of this microbial biopesticide in China. However, further research is essential for understanding its precise biocontrol mechanisms. In this paper, we report the complete genome sequence of HY96-2 and the results of a comparative genomic analysis between different P. polymyxa strains. The complete genome size of HY96-2 was found to be 5.75 Mb and 5207 coding sequences were predicted. HY96-2 was compared with seven other P. polymyxa strains for which complete genome sequences have been published, using phylogenetic tree, pan-genome, and nucleic acid co-linearity analysis. In addition, the genes and gene clusters involved in biofilm formation, antibiotic synthesis, and systemic resistance inducer production were compared between strain HY96-2 and two other strains, namely, SC2 and E681. The results revealed that all three of the P. polymyxa strains have the ability to control plant diseases via the mechanisms of colonization (biofilm formation), antagonism (antibiotic production), and induced resistance (systemic resistance inducer production). However, the variation of the corresponding genes or gene clusters between the three strains may lead to different antimicrobial spectra and biocontrol efficacies. Two possible pathways of biofilm formation in P. polymyxa were reported for the first time after searching the KEGG database. This study provides a scientific basis for the further optimization of the field applications and quality standards of industrial microbial biopesticides based on HY96-2. It may also serve as a reference for studying the differences in antimicrobial spectra and biocontrol capability between different biocontrol agents.

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“…Polymyxins contain six cationic inner membrane (5)(6)(7). Although LPS is absent in Gram-positive bacteria, recent studies showed that polymyxins can also kill their producer, P. polymyxa, in a manner mediated by both cell membrane damage and oxidative stress (8)(9)(10).…”

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confidence: 99%

Inactivation of Polymyxin by Hydrolytic Mechanism

Yin

Wang

Cheng

et al. 2019

Antimicrob Agents Chemother

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Polymyxins are nonribosomal peptide antibiotics used as the last-resort drug for treatment of multidrug-resistant Gram-negative bacteria. However, strains that are resistant to polymyxins have emerged in many countries. Although several mechanisms for polymyxin resistance have been well described, there is little knowledge on the hydrolytic mechanism of polymyxin. Here, we identified a polymyxininactivating enzyme from Bacillus licheniformis strain DC-1 which was produced and secreted into the medium during entry into stationary phase. After purification, sequencing, and heterologous expression, we found that the alkaline protease Apr is responsible for inactivation of polymyxins. Analysis of inactivation products demonstrated that Apr cleaves polymyxin E at two peptide bonds: one is between the tripeptide side chain and the cyclic heptapeptide ring, the other between L-Thr and L-␣-␥-diaminobutyric acid (L-Dab) within the cyclic heptapeptide ring. Apr is highly conserved among several genera of Gram-positive bacteria, including Bacillus and Paenibacillus. It is noteworthy that two peptidases S8 from Gram-negative bacteria shared high levels of sequence identity with Apr. Our results indicate that polymyxin resistance may result from inactivation of antibiotics by hydrolysis. KEYWORDS Bacillus licheniformis, alkaline protease, polymyxin resistance, polymyxininactivating enzyme, polymyxins L-␣-␥-diaminobutyric acid (L-Dab) residues (Fig. 1). Due to the higher affinity between L-Dab and lipid A, polymyxins displace divalent cations and bind to lipid A molecules, resulting in destabilization of the outer membrane. The hydrophobic domains of polymyxins (including the fatty acyl chain and D-Phe/D-Leu-L-Leu) insert between the acyl chains of lipid A and then enter the periplasm via a self-promoted uptake mechanism. Subsequently, polymyxins penetrate into the phospholipid bilayer of the RESULTSPolymyxins can be inactivated by Bacillus species. Studies from several decades ago indicated that colistin-inactivating enzymes are probably produced and secreted by the producer of colistin, P. polymyxa (20)(21)(22). To identify the colistin-inactivating enzyme, the cylinder-plate diffusion method was performed to screen colistin-degrading bacteria from our laboratory stocks of Bacillus strains. Escherichiacoli strain DH5␣ was used as a colistin-sensitive indicator strain. The addition of colistin (10,000 U/ml) resulted in an FIG 1 Chemical structure and degradation pathway of colistin. The amino acid positions are numbered in accordance with the discussion in the text. The amino acid at position 6 is D-Phe in polymyxin B. Both colistin and PMB are mixtures of structurally related compounds. Fatty acid, 6-methyloctanoic acid for colistin A and PMB 1 and 6-methylheptanoic acid for colistin B and PMB 2

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Oxidative Stress Induced by Polymyxin E Is Involved in Rapid Killing ofPaenibacillus polymyxa

Cited by 23 publications

References 40 publications

Spread of MCR-3 Colistin Resistance in China: An Epidemiological, Genomic and Mechanistic Study

Spread of MCR-3 Colistin Resistance in China: An Epidemiological, Genomic and Mechanistic Study

Complete Genome Sequence of Industrial Biocontrol Strain Paenibacillus polymyxa HY96-2 and Further Analysis of Its Biocontrol Mechanism

Inactivation of Polymyxin by Hydrolytic Mechanism

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