Odvezivanje sidra lipopolisaharida: sustavi za strukturne modifikacije lipida A nude dijagnostičke i terapijske opcije za borbu protiv polimiksinske rezistencije

Polymyxin antibiotics are the last resort for treating patients in intensive care units infected with multiple-resistant Gram-negative bacteria. Due to their polycationic structure, their mode of action is based on an ionic interaction with the negatively charged lipid A portion of the lipopolysaccharide (LPS). The most prevalent polymyxin resistance mechanisms involve covalent modifications of lipid A: addition of the cationic sugar 4-amino-L-arabinose (L-Ara4N) and/or phosphoethanolamine (pEtN). The modified structure of lipid A has a lower net negative charge, leading to the repulsion of polymyxins and bacterial resistance to membrane disruption. Genes encoding the enzymatic systems involved in these modifications can be transferred either through chromosomes or mobile genetic elements. Therefore, new approaches to resistance diagnostics have been developed. On another note, interfering with these enzymatic systems might offer new therapeutic targets for drug discovery. This literature review focuses on diagnostic approaches based on structural changes in lipid A and on the therapeutic potential of molecules interfering with these changes.Polimiksinski antibiotici zadnja su linija liječenja pacijenata u intenzivnim jedinicama liječenja koji su inficirani multiplorezistentnim gramnegativnim bakterijama. S obzirom na njihovu polikationsku strukturu, njihov mehanizam djelovanja temelji se na ionskoj interakciji s negativno nabijenim dijelom lipopolisaharida koji se naziva lipid A. Najčešći mehanizmi rezistencije na polimiksine uključuju kovalentne modifikacije lipida A: adiciju kationskog šećera 4-amino-L-arabinoze (L-Ara4N) i/ili fosfoetanoloamina (pEtN). Modificirana struktura lipida A sadrži niži neto negativni naboj, što prouzročuje odbojne sile između polimiksina i lipida A. To dovodi do bakterijske rezistencije na urušavanje integriteta stanične membrane. Geni koji kodiraju za enzimske sustave koji sudjeluju u navedenim modifikacijama mogu se prenositi kromosomima ili mobilnim genskim elementima. Stoga su i razvijeni novi pristupi dijagnostici rezistencije. Osim toga, u navedenim enzimskim sustavima postoje i moguće nove terapijske mete za razvoj lijekova. Ovaj pregledni rad usredotočuje se na dijagnostičke metode koje se temelje na strukturnim promjenama u lipidu A i na terapijskom potencijalu molekula koje interferiraju s navedenim strukturnim modifikacijama

Clinical utilization of colistin: a review of current clinical guidelines and research aiming to increase its clinical lifespan

Kolistin (polimiksin E) je ciklički kationski lipodekapeptidni antibiotik čiji mehanizam djelovanja uključuje narušavanje integriteta stanične membrane gram-negativnih bakterija. Kolistin je u kliničku praksu ušao sredinom 20. stoljeća, no njegova je primjena zbog nefrotoksičnosti i neurotoksičnosti napuštena već desetak godina nakon uvođenja u kliniku. U današnje vrijeme AMR postaje rastući zdravstveni problem zbog kojeg ponestaje terapijskih opcija za liječenje životno ugrožavajućih infekcija. Zato je kolistin pronašao svoje mjesto u klinici kao rezervni antibiotik s obzirom na to da je trenutno stopa rezistencije na kolistin relativno niska. S obzirom na to da je kolistin u humanoj medicini dugo bio opsolentan tek su 2019. godine donesene kliničke smjernice za uporabu kolistina koje su konsenzus relevantnih svjetskih kliničkih društava. Iz literature je uočen je trend porasta potrošnje kolistina u bolničkim sredinama u RH u periodu od 2011.-2021. Stoga zabrinjava i mogućnost porasta stope rezistencije na kolistin u bliskoj budućnosti. Kako bi se očuvala klinička efikasnost kolistina trenutno se razvijaju brze dijagnostičke metode za rano otkrivanje rezistencije na kolistin te se istražuju potencijalni adjuvantni terapeutici za kolistin.Colistin (polymyxin E) is a cyclic cationic lipodecapeptide antibiotic. Its mechanism of action involves the disruption of the cellular membrane of Gram-negative bacteria. Colistin has been discovered in 1947. Due to its high nephrotoxicity and neurotoxicity, its clinical use has been abandoned already a decade after its discovery. AMR is a growing public health issue, as there are currently few therapeutic options for treating life-threatening infections. Colistin has recently been re-introduced for clinical use due to its low resistance rates at the moment. In 2019., the first consensus clinical guidelines among relevant global clinical societies have been published. Literature has shown an increase in the clinical use of colistin in Croatian hospitals over the period 2011.-2021. Therefore, it is concerning that colistin resistance rates might increase over the following years. To increase colistin’s clinical lifespan, researchers are developing diagnostic methods for early resistance diagnostics and searching for potential adjuvant therapeutics for colistin

Clinical utilization of colistin: a review of current clinical guidelines and research aiming to increase its clinical lifespan

Kolistin (polimiksin E) je ciklički kationski lipodekapeptidni antibiotik čiji mehanizam djelovanja uključuje narušavanje integriteta stanične membrane gram-negativnih bakterija. Kolistin je u kliničku praksu ušao sredinom 20. stoljeća, no njegova je primjena zbog nefrotoksičnosti i neurotoksičnosti napuštena već desetak godina nakon uvođenja u kliniku. U današnje vrijeme AMR postaje rastući zdravstveni problem zbog kojeg ponestaje terapijskih opcija za liječenje životno ugrožavajućih infekcija. Zato je kolistin pronašao svoje mjesto u klinici kao rezervni antibiotik s obzirom na to da je trenutno stopa rezistencije na kolistin relativno niska. S obzirom na to da je kolistin u humanoj medicini dugo bio opsolentan tek su 2019. godine donesene kliničke smjernice za uporabu kolistina koje su konsenzus relevantnih svjetskih kliničkih društava. Iz literature je uočen je trend porasta potrošnje kolistina u bolničkim sredinama u RH u periodu od 2011.-2021. Stoga zabrinjava i mogućnost porasta stope rezistencije na kolistin u bliskoj budućnosti. Kako bi se očuvala klinička efikasnost kolistina trenutno se razvijaju brze dijagnostičke metode za rano otkrivanje rezistencije na kolistin te se istražuju potencijalni adjuvantni terapeutici za kolistin.Colistin (polymyxin E) is a cyclic cationic lipodecapeptide antibiotic. Its mechanism of action involves the disruption of the cellular membrane of Gram-negative bacteria. Colistin has been discovered in 1947. Due to its high nephrotoxicity and neurotoxicity, its clinical use has been abandoned already a decade after its discovery. AMR is a growing public health issue, as there are currently few therapeutic options for treating life-threatening infections. Colistin has recently been re-introduced for clinical use due to its low resistance rates at the moment. In 2019., the first consensus clinical guidelines among relevant global clinical societies have been published. Literature has shown an increase in the clinical use of colistin in Croatian hospitals over the period 2011.-2021. Therefore, it is concerning that colistin resistance rates might increase over the following years. To increase colistin’s clinical lifespan, researchers are developing diagnostic methods for early resistance diagnostics and searching for potential adjuvant therapeutics for colistin

Untying the anchor for the lipopolysaccharide: lipid A structural modification systems offer diagnostic and therapeutic options to tackle polymyxin resistance

Polymyxin antibiotics are the last resort for treating patients in intensive care units infected with multiple-resistant Gram-negative bacteria. Due to their polycationic structure, their mode of action is based on an ionic interaction with the negatively charged lipid A portion of the lipopolysaccharide (LPS). The most prevalent polymyxin resistance mechanisms involve covalent modifications of lipid A: addition of the cationic sugar 4-amino-L-arabinose (L-Ara4N) and/or phosphoethanolamine (pEtN). The modified structure of lipid A has a lower net negative charge, leading to the repulsion of polymyxins and bacterial resistance to membrane disruption. Genes encoding the enzymatic systems involved in these modifications can be transferred either through chromosomes or mobile genetic elements. Therefore, new approaches to resistance diagnostics have been developed. On another note, interfering with these enzymatic systems might offer new therapeutic targets for drug discovery. This literature review focuses on diagnostic approaches based on structural changes in lipid A and on the therapeutic potential of molecules interfering with these changes

Clinical utilization of colistin: a review of current clinical guidelines and research aiming to increase its clinical lifespan

Kolistin (polimiksin E) je ciklički kationski lipodekapeptidni antibiotik čiji mehanizam djelovanja uključuje narušavanje integriteta stanične membrane gram-negativnih bakterija. Kolistin je u kliničku praksu ušao sredinom 20. stoljeća, no njegova je primjena zbog nefrotoksičnosti i neurotoksičnosti napuštena već desetak godina nakon uvođenja u kliniku. U današnje vrijeme AMR postaje rastući zdravstveni problem zbog kojeg ponestaje terapijskih opcija za liječenje životno ugrožavajućih infekcija. Zato je kolistin pronašao svoje mjesto u klinici kao rezervni antibiotik s obzirom na to da je trenutno stopa rezistencije na kolistin relativno niska. S obzirom na to da je kolistin u humanoj medicini dugo bio opsolentan tek su 2019. godine donesene kliničke smjernice za uporabu kolistina koje su konsenzus relevantnih svjetskih kliničkih društava. Iz literature je uočen je trend porasta potrošnje kolistina u bolničkim sredinama u RH u periodu od 2011.-2021. Stoga zabrinjava i mogućnost porasta stope rezistencije na kolistin u bliskoj budućnosti. Kako bi se očuvala klinička efikasnost kolistina trenutno se razvijaju brze dijagnostičke metode za rano otkrivanje rezistencije na kolistin te se istražuju potencijalni adjuvantni terapeutici za kolistin.Colistin (polymyxin E) is a cyclic cationic lipodecapeptide antibiotic. Its mechanism of action involves the disruption of the cellular membrane of Gram-negative bacteria. Colistin has been discovered in 1947. Due to its high nephrotoxicity and neurotoxicity, its clinical use has been abandoned already a decade after its discovery. AMR is a growing public health issue, as there are currently few therapeutic options for treating life-threatening infections. Colistin has recently been re-introduced for clinical use due to its low resistance rates at the moment. In 2019., the first consensus clinical guidelines among relevant global clinical societies have been published. Literature has shown an increase in the clinical use of colistin in Croatian hospitals over the period 2011.-2021. Therefore, it is concerning that colistin resistance rates might increase over the following years. To increase colistin’s clinical lifespan, researchers are developing diagnostic methods for early resistance diagnostics and searching for potential adjuvant therapeutics for colistin