Information could be the key to winning the race against antibiotic resistance. If we lose, a UK-funded analysis predicts a frightening future where drug resistant bacterial infections kill more people worldwide than cancer.
The lack of progress in creating "new drugs for bad bugs" (a term coined by the European Commission's Innovative Medicines Initiative) is due, in part, to a lack of information--especially in one particular area known as translocation. Translocation is the action an antibiotic must take to penetrate the outer membrane of a bacterial cell in order to reach--and destroy--its target. In Escherichia coli (E. coli), for example, the OmpF channel (porin) provides a translocation pathway for small molecules, water, and ions inward and outward through the outer membrane.
So, which compounds are able to penetrate the outer membranes of bacteria, and which ones cannot?
That, according to Wonpil Im, is the mystery. Solving such a mystery by amassing the necessary information is especially important when it comes to the "Big Bads" of bacterial infections known as Gram-negative pathogens like "superbugs". These are the bacterial species that are resistant to multiple drugs and are increasingly resistant to most available antibiotics. The infections that result can be lethal. A few examples: some strains of the Gram-negative pathogen E. coli can cause serious food poisoning and certain strains of the Gram-negative bacteria called Vibrio cholera cause cholera, an infectious--and often fatal--disease of the small intestine.
Im, professor of biological sciences and bioengineering and Presidential Endowed Chair in Health - Science and Engineering at Lehigh University (Bethlehem, PA), is an expert in molecular simulation systems, which are very useful in the quest to solve such mysteries and provide the crucial missing information.
His CHARMM-GUI, a web-based graphical user interface designed to model complex biomolecular systems, aids in simulation design to produce models that usually require considerable experience and time (even several weeks) in just a few minutes or hours.
Now, through modeling and simulation, Im and his team have revealed the bilayer properties of 21 distinct Lipid A types from 12 Gram-negative bacterial species. Im and his colleagues from the University of Kansas, University of Maryland and Stockholm University investigate the differences and similarities of the membrane properties such as the area per lipid, the hydrophobic thickness, and acyl chain order. In addition, different neutralizing ion types (Ca2+, K+, and Na+) were considered, to examine the ion's influence on the membrane properties including lipid diffusion coefficients, ion residence times, and compressibility modulus that are experimentally comparable. Their results have been published today in an article in Biophysical Journal titled: "Bilayer Properties of Lipid A from Various Gram-negative Bacteria."
Lipid A is one of three regions that make up lipopolysaccharides (LPS), an integral component of the outer leaflet of the outer membrane of Gram-negative bacteria where they function as a shield and barrier to environmental threats to the bacterium. It is the LPS that make the outer membrane more impermeable to antibiotics. So, understanding and then manipulating LPS membrane stability could be an effective way to develop new Gram-negative antibiotics. Lipid A is the anchoring region of LPS--and is responsible for the toxic effects of Toxic Shock Syndrome and sepsis.
"The more information we can provide about the properties of the outer membrane of these so-called 'bad bugs,' the quicker researchers can determine which compounds might penetrate and effectively target a specific protein--even turn it off," said Im.
From the study: "...the resulting characteristics of different Lipid A obtained in this study form a basis toward the modeling and simulation of the outer membranes (with and without outer membrane proteins) of various Gram-negative bacteria. In particular, all Lipid A models in this study are available through LPS Modeler in CHARMM-GUI, so that these models can be used to further our understanding of the structure, dynamics, and function of various bacterial outer membranes."
"My dream," he adds "is that one day pharmaceutical companies could come to my lab with 100 compounds with the potential to kill a given Gram-negative bacteria and ask: which ones should we try? And we could tell them."
To advance this notion, Im has assembled a workshop titled "Workshop to Take Aim at Bacteria" to take place at Lehigh University on November 18, 2016. The workshop is designed to bring experts in research and policy (including a leader in the Innovative Medicines Initiative) to help speed antibiotic drug development.