All in the Timing

Resistant Microbes
New Study Shows Old Antibiotics May Still Be Effective Against Resistant Bacteria
June 11, 2015
Antibiotic resistant bacteria promise to be one of the great public health challenges of the next century. 
A 2014 study by the World Health Organization found resistant microbes (bacteria, fungi, parasites and viruses) in countries all over the world. The bacteria that cause tuberculosis, staph, gonorrhea and E. coli have all developed strains resistant to at least one antibiotic.
The race is already on to develop new antibiotics to combat resistant strains, but these illnesses evolve so quickly that new antibiotics can be rendered largely ineffective in a few years.
Researchers are looking at every new tool available to fight these resistant bacteria, but according to a new study from Duke University, using old tools in a new way may be able to kill resistant bacteria.
Graduate biomedical engineering student Hannah Meredith found that following an initial dose of antibiotics, a specifically timed second dose has an opportunity to attack resistant bacteria in a weakened state, essentially kicking them while they’re down. Initial lab results show that this method allows some older antibiotics to kill bacteria resistant to them.
Meredith studied a specific class of antibiotics called beta-lactams, a family which includes penicillin, amoxicillin and more than 50 other antibiotics. All those drugs have one important feature: the beta lactam ring. Beta Lactam Ring
Those five atoms spell doom for reproducing bacteria. All bacteria have a protective cell wall, and when a bacterium reproduces, it has to build more cell wall so that both daughter cells are protected. Beta lactams look very similar to cell wall building blocks, but when the bacteria pick them up, they can’t let go, leaving the bacteria unable to complete the cell wall. Not only does this keep the bacteria from reproducing, but it also causes a series of reactions that make the bacteria tear down the original cell wall, leaving it vulnerable to other attacks.
Beta Lactams Attack BacteriaOne way that bacteria can become resistant to these drugs is by developing a beta-lactamase enzyme, which as the name suggests, seeks out and breaks down beta-lactams. Beta-lactam drugs are still toxic to these bacteria, and they will still kill many of them, but the beta-lactamase enzymes degrade the drugs before they can wipe out the entire infection. The bacteria that survive the initial attack then reproduce to build the infection back up.
Meredith hypothesized that attacking the bacteria before they have a chance to build the infection back up, the antibiotics would so greatly outnumber the bacteria that the enzymes simply cannot keep up and the infection is eradicated. 
The trick, Meredith suggests, is knowing how long it takes a specific bacteria to recover from a specific antibiotic and administering a dose in that recovery period. Using a computer model, Meredith confirmed that attacking a resistant bacterial infection in its recovery period should be able to kill it.
To test this theory in the lab, Meredith began compiling a database of bacterial recovery times — essentially how long it takes a specific infection to recover from the attack of a specific antibiotic. Using those recovery times, Meredith has been able to kill off some resistant infections in petri dish experiments using older antibiotics. She published these findings in the journal PLOS Computational Biology.
This finding begs the question, if high doses of penicillin, for example, can kill bacteria resistant to penicillin, why not just pump sick people full of penicillin until the infection is cured. The answer is there are about 100 trillion little workers in our intestines that stand to lose quite a bit if we take too many antibiotics.
The bacteria in our intestines outnumber the cells in the human body 10 to 1 and they help us digest our food. They reproduce the same way as the bacteria that make us sick so antibiotics will also hurt our friendly gut bacteria. 
Our internal colony can deal with a few doses of antibiotics. Having 100 trillion microorganisms to start with means they tend to repopulate quickly and if a few die off, our bodies can still work normally. More doses and more frequent doses, however, can severely cripple that population, which throws the whole digestive system out of whack. 
Antibiotics, therefore, must be used carefully — giving the body enough to kill the infection but not enough to harm the gut flora. 
Meredith’s in vitro experiments showed that older antibiotics can still fight off resistant bacteria. Future in vivo studies will have to show they can effectively fight without causing too much damage in the process.
— Daniel Lane
Daniel Lane covers science, engineering, medicine and the environment in North Carolina.