Polymyxins, critical last-resort antibiotics, impact the distribution of membrane-bound divalent cations in the outer membrane of Gram-negative bacteria. We employed atomistic molecular dynamics simulations to model the effect of displacing these ions. Two polymyxin-sensitive and two polymyxin-resistant models of the outer membrane of Salmonella enterica were investigated. First, we found that the removal of all calcium ions induces global stress on the model membranes, leading to substantial membrane restructuring. Next, we used enhanced sampling methods to explore the effects of localized stress by displacing membrane-bound ions. Our findings indicate that creating defects in the membrane-bound ion network facilitates polymyxin permeation. Additionally, our study of polymyxin-resistant mutations revealed that divalent ions in resistant model membranes are less likely to be displaced, potentially contributing to the increased resistance associated with these mutations. Lastly, we compared results from all-atom molecular dynamics simulations with coarse-grained simulations, demonstrating that the choice of force field significantly influences the behavior of membrane-bound ions under stress.

• MeSH
• antibakteriální látky * farmakologie   chemie   metabolismus   MeSH
• bakteriální léková rezistence * MeSH
• buněčná membrána metabolismus   MeSH
• gramnegativní bakterie účinky léků   MeSH
• kationty dvojmocné metabolismus   MeSH
• mutace MeSH
• polymyxiny * farmakologie   chemie   metabolismus   MeSH
• Salmonella enterica účinky léků   metabolismus   MeSH
• simulace molekulární dynamiky * MeSH
• vápník metabolismus   MeSH
• vnější bakteriální membrána metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibakteriální látky * MeSH
• kationty dvojmocné MeSH
• polymyxiny * MeSH
• vápník MeSH

Antibiotic resistance is an ever-increasing global problem. Major commercial antibiotics often fail to fight common bacteria, and some pathogens have become multi-resistant. Polymyxins are potent bactericidal antibiotics against gram-negative bacteria. Known resistance to polymyxin includes intrinsic, mutational and adaptive mechanisms, with the recently described horizontally acquired resistance mechanisms. In this review, we present several strategies for bacteria to develop enhanced resistance to polymyxins, focusing on changes in the outer membrane, efflux and other resistance determinants. Better understanding of the genes involved in polymyxin resistance may pave the way for the development of new and effective antimicrobial agents. We also report novel in silico tested primers for PCR assay that may be able distinguish colistin-resistant isolates carrying the plasmid-encoded mcr genes and will assist in combating the spread of colistin resistance in bacteria.

• Klíčová slova
• LPS, colistin, polymyxin, resistance,
• MeSH
• antibakteriální látky farmakologie   MeSH
• bakteriální léková rezistence účinky léků   genetika   MeSH
• bakteriální proteiny účinky léků   genetika   MeSH
• gramnegativní bakteriální infekce farmakoterapie   genetika   MeSH
• kolistin farmakologie   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• polymyxiny farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antibakteriální látky MeSH
• bakteriální proteiny MeSH
• kolistin MeSH
• polymyxiny MeSH

Strains of the genusAcinetobacter, classified as genomic species 13BJ/14TU have been previously associated with human infections and resistance to colistin. To clarify the taxonomy of this provisional group, we investigated 24 strains that have been isolated from humans since the 1960s in 10 countries. The genus-wide analysis of the rpoB and gyrB sequences of all strains and whole-genome sequences of strains representing different rpoB/gyrB genotypes showed that the 24 strains formed a distinct monophyletic group within the so-called haemolytic clade of the genus Acinetobacter. The distinctness of the group at the species level was supported by the results of the cluster analysis of the whole-cell protein fingerprints generated by matrix-assisted laser desorption ionization-time-of-flight MS. The 24 strains had very similar metabolic features and could be distinguished from other members of the genus by the combination of strong haemolytic and proteolytic activities and the ability to oxidize d-glucose and grow on phenylacetate and/or l-phenylalanine. The minimum inhibitory concentrations of the 24 strains to colistin and polymyxin B ranged from 16 to 64 mgl-1 and from 4 to 32 mgl-1, respectively, so uniformly reaching the current clinical resistance breakpoint (4 mg l-1) for these drugs. Genus-wide comparison revealed that such a consistently high level of resistance to polymyxins is a unique feature among species of the genus Acinetobacter,which occur in humans. We conclude that genomic species 13BJ/14TU represents a biologically meaningful and medically relevant species, for which the name Acinetobacter colistiniresistens sp. nov. is proposed. The type strain is NIPH 2036T (=CCM 8641T=CIP 110478T=CCUG 67966T=CNCTC 7573T).

• MeSH
• Acinetobacter klasifikace   genetika   izolace a purifikace   MeSH
• bakteriální geny MeSH
• bakteriální léková rezistence * MeSH
• DNA bakterií genetika   MeSH
• fylogeneze * MeSH
• infekce bakteriemi rodu Acinetobacter mikrobiologie   MeSH
• lidé MeSH
• polymyxiny farmakologie   MeSH
• RNA ribozomální 16S genetika   MeSH
• sekvenční analýza DNA MeSH
• techniky typizace bakterií MeSH
• zastoupení bazí MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• DNA bakterií MeSH
• polymyxiny MeSH
• RNA ribozomální 16S MeSH

Antibiotic resistance among pathogenic bacteria is an ever-increasing issue worldwide. Unfortunately, very little has been achieved in the pharmaceutical industry to combat this problem. This has led researchers and the medical field to revisit past drugs that were deemed too toxic for clinical use. In particular, the cyclic cationic peptides polymyxin B and colistin, which are specific for Gram-negative bacteria, have been used as "last resort" antimicrobials. Before the 1980s, these drugs were known for their renal and neural toxicities; however, new clinical practices and possibly improved manufacturing have made them safer to use. Previously suggested to primarily attack the membranes of Gram-negative bacteria and to not easily select for resistant mutants, recent research exploring resistance and mechanisms of action has provided new perspectives. This review focuses primarily on the proposed alternative mechanisms of action, known resistance mechanisms, and how these support the alternative mechanisms of action.

• MeSH
• antibakteriální látky farmakologie   MeSH
• gramnegativní bakterie účinky léků   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• mnohočetná bakteriální léková rezistence * MeSH
• polymyxiny chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antibakteriální látky MeSH
• polymyxiny MeSH

Polymyxin B (PXB), a cyclic peptide antibiotic, in concentrations 0.1-3.0 mg/ml (0.08-4.0 mmol/l), inhibited the K+ efflux induced by opening of the Ca2+-activated K+ channel (the Gárdos effect) in intact human red blood cells. The inhibition was observed when the Gárdos effect was elicited by Ca2+ in the presence of vanadate, or propranolol, in ATP-depleted cells, and in A23187-treated cells. The inhibition of the Gárdos effect is caused neither by the inhibition of the anion channel by PXB nor by the inhibition of Ca2+ entry. It can be ascribed to the inhibition of the Ca2+-activated K+ channel. The mechanism of the inhibition remains to be elucidated.

• MeSH
• calcimycin farmakologie   MeSH
• draslík krev   MeSH
• erytrocyty účinky léků   metabolismus   MeSH
• fosforylace MeSH
• iontové kanály účinky léků   metabolismus   MeSH
• lidé MeSH
• polymyxin B farmakologie   MeSH
• polymyxiny farmakologie   MeSH
• propranolol farmakologie   MeSH
• proteinkinasa C antagonisté a inhibitory   metabolismus   MeSH
• vanadáty farmakologie   MeSH
• vápník farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• calcimycin MeSH
• draslík MeSH
• iontové kanály MeSH
• polymyxin B MeSH
• polymyxiny MeSH
• propranolol MeSH
• proteinkinasa C MeSH
• vanadáty MeSH
• vápník MeSH

Haemolysins of 4 strains of Pseudomonas aeruginosa producing different fractions [II, 2 + II, I + II + III] were studied. The production of specific antibodies was demonstrated making possible the immunoelectrophoretic record of the whole lysin and of the individual fractions. Tests on laboratory animals [mice, rabbits] showed a high degree lethal and dermonecrotic property of the lysin containing the fractions II + III and I + II + III.

• MeSH
• absorpce MeSH
• cytotoxické testy imunologické MeSH
• elektroforéza MeSH
• erytrocyty imunologie   MeSH
• gentamiciny farmakologie   MeSH
• hemolyziny analýza   MeSH
• imunodifuze MeSH
• imunoelektroforéza MeSH
• kolistin farmakologie   MeSH
• králíci imunologie   MeSH
• mikrobiální testy citlivosti MeSH
• myši MeSH
• ovce imunologie   MeSH
• polymyxiny farmakologie   MeSH
• Pseudomonas imunologie   MeSH
• specificita protilátek MeSH
• zvířata MeSH
• Check Tag
• králíci imunologie   MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• gentamiciny MeSH
• hemolyziny MeSH
• kolistin MeSH
• polymyxiny MeSH

• MeSH
• ampicilin farmakologie   MeSH
• antibakteriální látky aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• Bordetella pertussis účinky léků   MeSH
• chloramfenikol farmakologie   terapeutické užití   MeSH
• erythromycin farmakologie   MeSH
• gentamiciny farmakologie   MeSH
• Haemophilus influenzae účinky léků   MeSH
• hemofilové infekce farmakoterapie   MeSH
• kanamycin farmakologie   MeSH
• karbenicilin farmakologie   MeSH
• neomycin farmakologie   MeSH
• peniciliny farmakologie   MeSH
• pertuse farmakoterapie   MeSH
• polymyxiny farmakologie   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ampicilin MeSH
• antibakteriální látky MeSH
• chloramfenikol MeSH
• erythromycin MeSH
• gentamiciny MeSH
• kanamycin MeSH
• karbenicilin MeSH
• neomycin MeSH
• peniciliny MeSH
• polymyxiny MeSH

• MeSH
• antibakteriální látky farmakologie   MeSH
• antibiotická rezistence * MeSH
• bakteriologické techniky MeSH
• chloramfenikol farmakologie   MeSH
• chlortetracyklin farmakologie   MeSH
• Escherichia coli účinky léků   metabolismus   MeSH
• feces analýza   MeSH
• neomycin farmakologie   MeSH
• nitrofurantoin farmakologie   MeSH
• oxytetracyklin farmakologie   MeSH
• polymyxiny farmakologie   MeSH
• potravinářské přísady MeSH
• prasata MeSH
• streptomycin farmakologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibakteriální látky MeSH
• chloramfenikol MeSH
• chlortetracyklin MeSH
• neomycin MeSH
• nitrofurantoin MeSH
• oxytetracyklin MeSH
• polymyxiny MeSH
• potravinářské přísady MeSH
• streptomycin MeSH

• MeSH
• Bacillus cereus účinky léků   MeSH
• izotopy uhlíku MeSH
• leucin metabolismus   MeSH
• lysin farmakologie   MeSH
• polymyxiny farmakologie   MeSH
• protaminy farmakologie   MeSH
• spory účinky léků   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• izotopy uhlíku MeSH
• leucin MeSH
• lysin MeSH
• polymyxiny MeSH
• protaminy MeSH