Revealing Insights into Natural Products Against mcr-1-Producing Bacteria

2021 ◽  
Vol 22 ◽  
Author(s):  
Ana Beatriz Souza Flor dos Santos ◽  
Manuele Figueiredo da Silva ◽  
João Xavier de Araújo-Júnior ◽  
Edeildo Ferreira da Silva-Júnior
Keyword(s):  
Lipid A ◽  
Bacterial Resistance ◽  
Polymyxin B ◽  
Resistance Mechanisms ◽  
Synergistic Action ◽  
Gram Negative Bacteria ◽  
Amino Acid Residues ◽  
Critical Amino Acid ◽  
Natural Agents ◽  
Global Concern

: Bacterial resistance has become a major global concern, affecting about 500,000 individuals in 22 countries. Thus, it is clear that Gram-negative bacteria have been receiving more attention in this scenario. These bacteria perform several resistance mechanisms, such as modifying lipid A from lipopolysaccharides as a product of the mcr-1 gene expression. This gene was initially identified in animals; however, it quickly spread to humans, spreading to 70 countries. Mcr-1 gene attributes resistance to polymyxin B and colistin, which are drugs established as the last alternative to combat Enterobacteriaceae bacteria. Notwithstanding the prevalence and lack of antibiotic therapies for such bacteria, this article aimed to compile information about natural compounds against the resistance attributed by this gene, including the activity of isolated colistin or its associations with other antibiotics. Among the studies that evaluated colistin's synergistic action with other compounds, azidothymidine and isoalantholactone stood out. On the other hand, the paenipeptin 1 analog showed satisfactory activities when associated with other antibiotics. Besides, it is worth mentioning that molecular docking results between ostole and eugenol toward phosphoethanolamine transferase MCR-1 revealed that these compounds could interact with critical amino acid residues for the catalytic action of this enzyme. Based on this, natural agents' role is evident against infections caused by mcr-1-positive bacteria, directly contributing to the development of new effective pharmacotherapies.

Restriction of gut-derived endotoxin impairs DNA synthesis for liver regeneration

1985 ◽  
Vol 249 (5) ◽  
pp. R563-R569 ◽  
Author(s):  
R. P. Cornell
Keyword(s):  
Liver Resection ◽  
Dna Synthesis ◽  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Lipid A ◽  
Subcutaneous Administration ◽  
Endotoxin Tolerance ◽  
Polymyxin B ◽  
Gram Negative Bacteria ◽  
Higher Doses

The influence of restricting gut-derived endotoxin availability on liver regeneration after partial hepatectomy was evaluated. Partial hepatectomy was performed by 67% liver resection of ether-anesthetized rats. Liver regeneration was quantified after partial hepatectomy by [3H]thymidine incorporation into hepatic DNA; endotoxemia due to absorption of endogenous endotoxin from the gut into the portal circulation was determined by qualitative lysate assay of perchloric acid-extracted plasma samples, and plasma levels of the hepatotrophic factors insulin and glucagon were measured by radioimmunoassay. Treatments to restrict gut-derived endotoxin included chronic gavage with neomycin and cefazolin for gut sterilization, chronic gavage with cholestyramine to bind endotoxin within the gut, subcutaneous administration of polymyxin B to neutralize the lipid A portion of circulating endotoxin, intraperitoneal induction of endotoxin tolerance by progressively higher doses of endotoxin, and experimentation with isolator-reared defined flora Fisher rats that were Gram-negative bacteria deficient and therefore endotoxin deficient. All treatments to restrict endogenous endotoxin impaired DNA synthesis in regenerating livers particularly 21 h posthepatectomy when replication was increasing most rapidly in normal rats. We hypothesize that impairment of DNA synthesis after partial hepatectomy in endotoxin-restricted animals was due to the observed lack of normal systemic endotoxemic as well as hyperinsulinemic and hyperglucagonemic responses to 67% liver resection.

scholarly journals A Molecular Perspective on Colistin and Klebsiella pneumoniae: Mode of Action, Resistance Genetics, and Phenotypic Susceptibility

Diagnostics ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1165
Author(s):  
Rita Elias ◽  
Aida Duarte ◽  
João Perdigão
Keyword(s):  
Klebsiella Pneumoniae ◽  
Mode Of Action ◽  
Lipid A ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Drug Susceptibility Testing ◽  
Gram Negative Bacteria ◽  
Colistin Resistance ◽  
Gram Negative

Klebsiella pneumoniae is a rod-shaped, encapsulated, Gram-negative bacteria associated with multiple nosocomial infections. Multidrug-resistant (MDR) K. pneumoniae strains have been increasing and the therapeutic options are increasingly limited. Colistin is a long-used, polycationic, heptapeptide that has regained attention due to its activity against Gram-negative bacteria, including the MDR K. pneumoniae strains. However, this antibiotic has a complex mode of action that is still under research along with numerous side-effects. The acquisition of colistin resistance is mainly associated with alteration of lipid A net charge through the addition of cationic groups synthesized by the gene products of a multi-genic regulatory network. Besides mutations in these chromosomal genes, colistin resistance can also be achieved through the acquisition of plasmid-encoded genes. Nevertheless, the diversity of molecular markers for colistin resistance along with some adverse colistin properties compromises the reliability of colistin-resistance monitorization methods. The present review is focused on the colistin action and molecular resistance mechanisms, along with specific limitations on drug susceptibility testing for K. pneumoniae.

scholarly journals mig-14 Is a Salmonella Gene That Plays a Role in Bacterial Resistance to Antimicrobial Peptides

2002 ◽  
Vol 184 (12) ◽  
pp. 3203-3213 ◽  
Author(s):  
Igor E. Brodsky ◽  
Robert K. Ernst ◽  
Samuel I. Miller ◽  
Stanley Falkow
Keyword(s):  
Antimicrobial Peptides ◽  
Lipid A ◽  
Bacterial Resistance ◽  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
Polymyxin B ◽  
Negative Resistance ◽  
Low Magnesium ◽  
Bacterial Proliferation ◽  
Serovar Typhimurium

ABSTRACT It was previously demonstrated that the mig-14 gene of Salmonella enterica serovar Typhimurium is necessary for bacterial proliferation in the liver and spleen of mice following intragastric inoculation and that mig-14 expression, which is induced within macrophages, is under the control of the global regulator PhoP. Here we demonstrate that the mig-14 promoter is induced by growth in minimal medium containing low magnesium or acidic pH, consistent with regulation by PhoP. In addition, mig-14 is strongly induced by polymyxin B, protamine, and the mammalian antimicrobial peptide protegrin-1. While phoP is necessary for the induction of mig-14 in response to protamine and protegrin, mig-14 is still induced by polymyxin B in a phoP background. We also demonstrate that mig-14 is necessary for resistance of S. enterica serovar Typhimurium to both polymyxin B and protegrin-1. Gram-negative resistance to a variety of antimicrobial peptides has been correlated with modifications of lipopolysaccharide structure. However, we show that mig-14 is not required for one of these modifications, the addition of 4-aminoarabinose to lipid A. Additionally, sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of wild-type and mig-14 lipopolysaccharide also shows no detectable differences between the two strains. Therefore, mig-14 contributes to Salmonella resistance to antimicrobial peptides by a mechanism that is not yet fully understood.

scholarly journals LpxT-Dependent Phosphorylation of Lipid A in Escherichia coli Increases Resistance to Deoxycholate and Enhances Gut Colonization

2021 ◽  
Vol 12 ◽  
Author(s):  
Xudong Tian ◽  
Guillaume Manat ◽  
Elise Gasiorowski ◽  
Rodolphe Auger ◽  
Samia Hicham ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Cell Surface ◽  
Lipid A ◽  
Negative Charge ◽  
Polymyxin B ◽  
Gram Negative Bacteria ◽  
Bacterial Cells ◽  
Gram Negative ◽  
E Coli ◽  
Gut Colonization

The cell surface of Gram-negative bacteria usually exhibits a net negative charge mostly conferred by lipopolysaccharides (LPS). This property sensitizes bacterial cells to cationic antimicrobial peptides, such as polymyxin B, by favoring their binding to the cell surface. Gram-negative bacteria can modify their surface to counteract these compounds such as the decoration of their LPS by positively charged groups. For example, in Escherichia coli and Salmonella, EptA and ArnT add amine-containing groups to the lipid A moiety. In contrast, LpxT enhances the net negative charge by catalyzing the synthesis of tri-phosphorylated lipid A, whose function is yet unknown. Here, we report that E. coli has the intrinsic ability to resist polymyxin B upon the simultaneous activation of the two component regulatory systems PhoPQ and PmrAB by intricate environmental cues. Among many LPS modifications, only EptA- and ArnT-dependent decorations were required for polymyxin B resistance. Conversely, the acquisition of polymyxin B resistance compromised the innate resistance of E. coli to deoxycholate, a major component of bile. The inhibition of LpxT by PmrR, under PmrAB-inducing conditions, specifically accounted for the acquired susceptibility to deoxycholate. We also report that the kinetics of intestinal colonization by the E. coli lpxT mutant was impaired as compared to wild-type in a mouse model of infection and that lpxT was upregulated at the temperature of the host. Together, these findings highlight an important function of LpxT and suggest that a tight equilibrium between EptA- and LpxT-dependent decorations, which occur at the same position of lipid A, is critical for the life style of E. coli.

scholarly journals Is lipopolysaccharide a factor in infectivity of Chlamydia trachomatis?

2008 ◽  
Vol 57 (3) ◽  
pp. 261-266 ◽  
Author(s):  
Sanaa Fadel ◽  
Adrian Eley
Keyword(s):  
Chlamydia Trachomatis ◽  
Epithelial Cells ◽  
Host Cell ◽  
Lipid A ◽  
Polymyxin B ◽  
Gram Negative Bacteria ◽  
Dependent Manner ◽  
Gram Negative ◽  
Major Surface ◽  
Dose Dependent

Lipopolysaccharide (LPS) is a major surface component of Chlamydia trachomatis, as with all Gram-negative bacteria. The effect of C. trachomatis LPS on C. trachomatis infectivity of human epithelial cells was investigated. C. trachomatis LPS and C. trachomatis LPS antibody significantly reduced infectivity, mostly in a dose-dependent manner. As the structure of LPS in C. trachomatis is simple and consists only of lipid A and 3-deoxy-d-manno-octulosonic acid (Kdo), we investigated whether lipid A or Kdo was inhibitory to chlamydial infectivity. Polymyxin B, as a lipid A inhibitor, and Kdo considerably reduced C. trachomatis infectivity. With all the LPS inhibitors used, there was greater inhibition against serovar E than serovar LGV. These results suggest a role for LPS in chlamydial infectivity. Elucidation of how LPS acts in infectivity and identification of host-cell receptors would help in understanding pathogenicity.

scholarly journals PmrD Is Required for Modifications to Escherichia coli Endotoxin That Promote Antimicrobial Resistance

2015 ◽  
Vol 59 (4) ◽  
pp. 2051-2061 ◽  
Author(s):  
Erica J. Rubin ◽  
Carmen M. Herrera ◽  
Alexander A. Crofts ◽  
M. Stephen Trent
Keyword(s):  
Escherichia Coli ◽  
Protein Interactions ◽  
Lipid A ◽  
Bacterial Resistance ◽  
Functional Divergence ◽  
Polymyxin B ◽  
Growth Conditions ◽  
Wild Type ◽  
Content Type ◽  
E Coli

ABSTRACTInSalmonella enterica, PmrD is a connector protein that links the two-component systems PhoP-PhoQ and PmrA-PmrB. WhileEscherichia coliencodes a PmrD homolog, it is thought to be incapable of connecting PhoPQ and PmrAB in this organism due to functional divergence from theS. entericaprotein. However, our laboratory previously observed that low concentrations of Mg2+, a PhoPQ-activating signal, leads to the induction of PmrAB-dependent lipid A modifications in wild-typeE. coli(C. M. Herrera, J. V. Hankins, and M. S. Trent, Mol Microbiol 76:1444–1460, 2010,http://dx.doi.org/10.1111/j.1365-2958.2010.07150.x). These modifications include phosphoethanolamine (pEtN) and 4-amino-4-deoxy-l-arabinose (l-Ara4N), which promote bacterial resistance to cationic antimicrobial peptides (CAMPs) when affixed to lipid A. Here, we demonstrate thatpmrDis required for modification of the lipid A domain ofE. colilipopolysaccharide (LPS) under low-Mg2+growth conditions. Further, RNA sequencing shows thatE. colipmrDinfluences the expression ofpmrAand its downstream targets, including genes coding for the modification enzymes that transfer pEtN andl-Ara4N to the lipid A molecule. In line with these findings, apmrDmutant is dramatically impaired in survival compared with the wild-type strain when exposed to the CAMP polymyxin B. Notably, we also reveal the presence of an unknown factor or system capable of activatingpmrDto promote lipid A modification in the absence of the PhoPQ system. These results illuminate a more complex network of protein interactions surrounding activation of PhoPQ and PmrAB inE. colithan previously understood.

Bacterial Resistance: Antibiotics of Last Generation used in Clinical Practice and the Arise of Natural Products as New Therapeutic Alternatives

2020 ◽  
Vol 26 (8) ◽  
pp. 815-837 ◽  
Author(s):  
Rúbia C.G. Corrêa ◽  
Sandrina A. Heleno ◽  
Maria J. Alves ◽  
Isabel C.F.R. Ferreira
Keyword(s):  
Natural Products ◽  
Natural Resources ◽  
Bacterial Resistance ◽  
Antimicrobial Agents ◽  
Resistance Mechanisms ◽  
Critical Discussion ◽  
Public Health Issue ◽  
Resistant Bacteria ◽  
Natural Agents ◽  
Development Of Resistance

Bacterial resistance to therapeutical drugs has been a serious issue over the last decades. In fact, the quick development of resistance mechanisms by the microorganisms has been fatal for millions of people around the world, turning into a public health issue. The major cause of the resistance mechanisms is the overuse of antimicrobials. European countries try to implement mechanisms to overcome antimicrobial resistance in the community through the rational use of antimicrobials. The scientific community has been exhaustively dedicated to the discovering of new, safer and efficient drugs, being the exploitation of natural resources, mainly plants and fungi, considered as a hot topic in the field of antimicrobial agents. Innumerous reports have already shown the promising capacity of natural products or molecules extracted from these natural resources, to act as bacteriostatic and bactericidal agents. More importantly, these natural agents present significantly lower harmful effects. Bearing that in mind, this review aims at giving a contribution to the knowledge about the synthetic antibiotics of the last generation. Moreover, it is intended to provide information about the last advances regarding the discovery of new antimicrobial agents. Thus, a compilation of the chemical characteristics, efficiency, harmful outcomes and resistance mechanisms developed by the microorganisms can be consulted in the following sections together with a critical discussion, in line with the recent approaches. Furthermore, modern strategies for the prospection of novel anti-infective compounds for tackling resistant bacteria have been considered as also a current synopsis of plants and mushrooms with relevant antimicrobial potentials.

scholarly journals Polymyxins: Antibacterial Activity, Susceptibility Testing, and Resistance Mechanisms Encoded by Plasmids or Chromosomes

2017 ◽  
Vol 30 (2) ◽  
pp. 557-596 ◽  
Author(s):  
Laurent Poirel ◽  
Aurélie Jayol ◽  
Patrice Nordmann
Keyword(s):  
Susceptibility Testing ◽  
Clinical Medicine ◽  
Current Knowledge ◽  
Relevant Information ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Phenotypic Methods

SUMMARY Polymyxins are well-established antibiotics that have recently regained significant interest as a consequence of the increasing incidence of infections due to multidrug-resistant Gram-negative bacteria. Colistin and polymyxin B are being seriously reconsidered as last-resort antibiotics in many areas where multidrug resistance is observed in clinical medicine. In parallel, the heavy use of polymyxins in veterinary medicine is currently being reconsidered due to increased reports of polymyxin-resistant bacteria. Susceptibility testing is challenging with polymyxins, and currently available techniques are presented here. Genotypic and phenotypic methods that provide relevant information for diagnostic laboratories are presented. This review also presents recent works in relation to recently identified mechanisms of polymyxin resistance, including chromosomally encoded resistance traits as well as the recently identified plasmid-encoded polymyxin resistance determinant MCR-1. Epidemiological features summarizing the current knowledge in that field are presented.

scholarly journals Susceptibility of Colistin-Resistant, Gram-Negative Bacteria to Antimicrobial Peptides and Ceragenins

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Marjan M. Hashemi ◽  
John Rovig ◽  
Scott Weber ◽  
Brian Hilton ◽  
Mehdi M. Forouzan ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Antimicrobial Peptides ◽  
Lipid A ◽  
Resistance Mechanisms ◽  
Clinical Isolates ◽  
Cross Resistance ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Content Type

ABSTRACT The susceptibility of colistin-resistant clinical isolates of Klebsiella pneumoniae to ceragenins and antimicrobial peptides (AMPs) suggests that there is little to no cross-resistance between colistin and ceragenins/AMPs and that lipid A modifications are found in bacteria with modest changes in susceptibility to ceragenins and with high levels of resistance to colistin. These results suggest that there are differences in the resistance mechanisms to colistin and ceragenins/AMPs.

scholarly journals Release of the Lipopolysaccharide Deacylase PagL from Latency Compensates for a Lack of Lipopolysaccharide Aminoarabinose Modification-Dependent Resistance to the Antimicrobial Peptide Polymyxin B in Salmonella enterica

2007 ◽  
Vol 189 (13) ◽  
pp. 4911-4919 ◽  
Author(s):  
Kiyoshi Kawasaki ◽  
Kotaro China ◽  
Masahiro Nishijima
Keyword(s):  
Salmonella Enterica ◽  
Lipid A ◽  
Bacterial Resistance ◽  
Biological Significance ◽  
Regulatory System ◽  
Polymyxin B ◽  
Expression Plasmid ◽  
Loss Of Resistance ◽  
Anionic Charge

ABSTRACT Salmonella enterica modifies its lipopolysaccharide (LPS), including the lipid A portion, to adapt to its environments. The lipid A 3-O-deacylase PagL exhibits latency; deacylation of lipid A is not usually observed in vivo despite the expression of PagL, which is under the control of a two-component regulatory system, PhoP-PhoQ. In contrast, PagL is released from latency in pmrA and pmrE mutants, both of which are deficient in aminoarabinose-modified lipid A, although the biological significance of this is not clear. The attachment of aminoarabinose to lipid A decreases the net anionic charge at the membrane's surface and reduces electrostatic repulsion between neighboring LPS molecules, leading to increases in bacterial resistance to cationic antimicrobial peptides, including polymyxin B. Here we examined the effects of the release of PagL from latency on resistance to polymyxin B. The pmrA pagL and pmrE pagL double mutants were more susceptible to polymyxin B than were the parental pmrA and pmrE mutants, respectively. Furthermore, introduction of the PagL expression plasmid into the pmrA pagL double mutant increased the resistance to polymyxin B. In addition, PagL-dependent deacylation of lipid A was observed in a mutant in which lipid A could not be modified with phosphoethanolamine, which partly contributes to the PmrA-dependent resistance to polymyxin B. These results, taken together, suggest that the release of PagL from latency compensates for the loss of resistance to polymyxin B that is due to a lack of other modifications to LPS.

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