Targeting dormant bacteria

Antibiotics are effective against bacteria because they target and knock out specific functions that are vital for bacterial survival. As most bacterial infections involve rapid growth and division of the invading bacteria, many commercial antibiotics currently target metabolically active cells, by blocking enzymes needed for growth, reproduction, or cell wall synthesis. While these will kill acute bacterial infections they are often far less effective against dormant bacteria in longer-term persistent infections.

Rather than targeting metabolic enzymes, the current strategies being explored to combat dormant bacteria target either the membrane, or membrane bound proteins. Both of these approaches destabilise the bacterial membrane and help to break the cell apart and can act against processes such as energy synthesis which occur in both active and dormant cells.

a=targeting important metabolic proteins in the membrane. b=targeting the actual cell-membrane. Picture is copywrite me :p

In eukaryotic cells, such as the cells of plants and animals, the enzymes that create energy for the cell are kept safely hidden away in specialised intracellular compartments, such as mitochondria. As energy production requires an ion gradient across a membrane, these compartments all have sets of internal membranes. Bacteria however do not have this luxury, and instead have all their metabolic enzymes in the outer cell membrane, as this is the only membrane they have. Inhibitors of energy metabolism can therefore bind directly to target enzymes in the membrane involved in the production of energy. This can be highly effective against cells whose interior is hard to get into, such as Mycobacterium tuberculosis which lurks inside tuberculosis granulomas. Even in the absence of growth, cells still require a minimal energy input to survive, so blocking off these enzymes kills both dormant and active cells.

Drug developed to help combat TB by attacking cell membrane metabolic enzymes. This drug is currently in stage three clinical trials.

The membrane-targeting drugs act directly on the lipid bilayer that surrounds the bacterial cell, breaking it up and destroying the bacterial cellular integrity. Although human cells are also surrounded by lipid bilayers they have fewer negatively charged phosopholipids and also contain cholesterol (not present in bacterial membranes) allowing membrane-targeted drugs to be specific for human pathogens rather than killing surrounding human cells. The drugs that are used to attack the cell wall can vary hugely in size and structure but they all share one common property; they are highly lipophilic (i.e they are attracted to lipids). This allows them to interact with the cell membrane and break it apart.

Lipophilic drug capible of targeting bacterial cell membranes

There’s something about those molecular diagrams of drugs that I love. I think it’s my biochemical background. I’m never totally happy with a schematic until I can see how the chemicals are interacting on a molecular scale.

As well as being useful against dormant bacteria these new antimicrobials show promise as strategies for dealing with arising antibiotic resistance. Bacteria can evolve to cope with as many challenges as are thrown at them, but hopefully it should take them a little longer learn to survive entirely without a cell wall…

Although there are some that can do that already.

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Hurdle JG, O'Neill AJ, Chopra I, & Lee RE (2011). Targeting bacterial membrane function: an underexploited mechanism for treating persistent infections. Nature reviews. Microbiology, 9 (1), 62-75 PMID: 21164535

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