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Starving-Bacteria Antibiotic Resistance Can Now Be Overcomed

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Starving-Bacteria Antibiotic Resistance Can Now Be Overcomed

Nowadays clinicians encounter more and more antibiotic-resistant infections even though the antibiogram shows sensitivity of the certain bacteria to medication. This impossibility to cure antibiotic sensible infections is quite a paradox and doctors are facing it each day in practice. A possible explanation of this resistance is that, during the infection, the bacteria lacks nutrients. Bacteria which lack key nutrients for its development tends to be resistant to almost every type of antibiotics class, even the ones it haven’t encountered before in order to develop resistance.

A study published in Science magazine this week, tries to explain what exactly leads to starvation-induced antibiotic resistance, and how could clinicians overcome it.

Bacteria is usually lacking key nutrients when body nutrient supplies are exhausted or when they tend to form a tightly assembled group known as biofilm according to Dr. Dao Nguyen from the McGill Univeristy.

Biofilms are groups of bacteria covered with a slimy coating, form of organization that can be found both in human tissues (where they cause the infection) or in the natural environment of the bacteria. This biofilm protects the bacteria from the bactericide action of antibiotics making them able to tolerate extremely high doses of antibiotics that would normally kill them.

Sensitive Bacteria

Sensitive Bacteria

Bacteria that are living outside the biofilm can receive more nutrients that are diffusing in, leading to starvation of the bacteria that are living inside clusters, rendering them highly resistant to antibiotics, said Dr. Pradeep Singh, senior author of the study. Most antibiotics target cellular functions that are active during bacterial growth, but when bacteria stop the growing process these cellular targets can not be attacked by the active substances, leading therefore to resistance. This is quite a discovery but it also leads to a major dilemma: in order to sensitive bacteria, growth stimulation would be required, and this is not an option during human infections.

Dr. Dao Nguyen and  Dr. Pradeep Singh then turned their attention to another possible mechanism.

It is not a new thing that bacteria issue certain chemical compounds when they sense that nutrients are running low. These chemicals warn bacteria and determines them to prepare their metabolic pathways for starvation. Could these chemicals be also the cause of the antibiotic resistance effect?

The team genetically created bacteria that lack these signal compounds, determined them to enter starvation and then measured, using an antibiogram, the antibiotic resistance of these bacteria. The results were amazing. Starved bacteria that were not alerted by chemical compounds were thousands of times more sensitive to antibiotics, even if they stopped growing and the antibiotics were lacking active cellular targets.

This is a major breakthrough as this could mean that antibiotic resistance of starved bacteria could now be inhibited. This study also demonstrated that protection of starved bacteria is provided by chemical compounds released when nutrients are running low.

After these results scientists tried to answer two key questions.

First does the starvation alarm actually leads to bacterial resistance in human infections? In order to prove this the team tested the sensibility of bacteria , unable to sense when nutrients are running low, in mice infections, isolates taken from different patients and laboratory cultures. The result was unchanged: unaware of starvation bacteria were by far more sensitive to antibiotic treatment.

The second question was targeting the exact mechanism of the resistance process. What does actually leads to extreme antibiotic resistance in starved bacteria?

The scientists found that the bacteria were protected against free radicals (toxic forms of O2) , the exact mechanism of action of antibiotics (they generate oxygen free radicals that kill the bacterium).