Amidst growing concern about antibiotics resistance, a new class of antibiotics may help in the fight against gram-negative bacteria.
Gram-negative bacteria such as Acinetobacter baumannii, Enterobacteriaceae and pseudomonas aeruginosa, are raising concern for human health. Globally, gram-negative bacteria have displayed increasing resistance to carbapenem and cephalosporin antibiotics. New treatments for gram-negative bacteria are needed, particularly as the resistance grows to the last resort antibiotics colistin.
The last new class of antibiotics introduced to the market against gram-negative bacteria was the fluroquinolones in the 1960s. According to a study, a Swiss research team led by experts from the University of Zurich has discovered a new family of synthetic antibiotics with broad-spectrum anti-gram-negative antimicrobial activity including against all of the gram-negative members of the ESKAPE pathogen.
The new class of chimeric peptidomimetic antibiotics known as OMPTA (Outer Membranes Protein Targeting Antibiotics)’ functions by employing a unique mechanism that targets the outer membranes of gram-negative bacteria.
The new antibiotics interact with essential outer membranes protein in gram-negative bacteria. UZH department of chemistry and co-head of the John Robinson said in a statement “according to our results, the antibiotics bind to complete flu-like substance called lipopolysaccharides and to Bam A, an essential protein of the outer membrane of gram-negative bacteria.
The outer membrane of gram-negative bacteria “comprises an asymmetric bilayer with glycerophospholipids in the inner leaflet and lipopolysaccharide (LPS) in the outer leaflet”, the study authors wrote.“ This unique permeability barrier protects the bacteria from toxic environment factors such as antibiotics and contains many integral B-barrel outer membrane proteins (OMPS) which are required for the biogenesis of the membrane”.
Investigators obtained a range of clinical isolation from University Hospital Basel and the IHMA collection that were collected between 2012 to 2017. Eight compounds were analysed. Chimera 3 and 4 had a marked effect on Escherichia coli membrane structure, which showed extra membranelike material, membrane detachment and the appearance of vacuoles.
Electron microscopy revealed that cells treated with compounds 3 and 4 showed collapsed membranes and extracellular “ knob-like structures”, suggesting that both of the chimera perturb bacterial membranes.
Compound 3,4,7 and 8 were shown to be bactericidal against several gram-negative pathogens including multidrug-resistant strains. Study authors hope future research will help determine how the binding of the chimeras to Bam A causes downstream bactericidal activity.
In considering how the bactericidal activity functions the investigators hypothesized that one possibility is that binding inhibits foldase activity to BAM complex, the resulting incorrectly folded OMPs when misplaced, the inner membrane may lead to cell permeabilization and death.
Alternatively, another possibility identified was that binding of the chimera to Bam A provides an additional binding site in the outer membrane that enhances a permeabilizing effect mediated by polymyxin macrocycle and helps these antibiotics to avoid LPS modification resistance mechanisms. Polyphor, a Swiss biopharmaceutical company announced that the lead molecule of the new OMPTA class is currently in preclinical toxicology studies.
Study authors said that a lead candidate based on these derivatives has pending future clinical studies. The potential to address life-threatening infections caused by gram-negative pathogens and thus to resolve the considerable unmet medical need.
By: Peace Chigozie