There have been innumerable efforts throughout history to discover more effective manners to offset the deadly effects of tuberculosis, considered one of the greatest enemies of humanity. This antique killer, also known in the Middle Ages as the “Kings evil” and in the eighteenth century as the “white plague” kills 1.6 million people around the world, including 1,600 in Colombia.
As malaria, tuberculosis (TB) is a disease linked to poverty and affects people especially with human immunodeficiency virus (HIV), incarcerated people or street dwellers. According to the World Health Organization (WHO) Global Tuberculosis Report 2018, in the countries with greater income, there were less than 10 new TB cases for every 100,000 inhabitants, while in poorer countries incidence is between 150 and 400 for every 100,000 inhabitants.
In Colombia, statistics of the National Health Institute show that the Provinces of Amazonas, Guaviare, Casanare, Chocó, and Risaralda are the most affected with cases that passed from 24 for every 100,000 inhabitants in 2014 to 26.3 in 2017.
The increase in cases (16,000 in Colombia last year and 10 million in the world) is one of the reasons that 163 United Nations country-members committed to reducing death rates in 90% before the year 2030; a hard task to undertake if drug resistance developed by the bacterium Mycobacterium tuberculosis is one of the main obstacles to battle against the disease.
Multi-resistant drug tuberculosis is a public health crisis and a threat to health security. WHO calculations show that in 2018 there were 558,000 new cases of rifampicin-resistant TB of 82% of people with the disease. Therefore, developing new compounds against TB continues to be a crucial task for science.
Since a decade ago, Universidad Nacional de Colombia (UNal) Science-Biochemistry Ph.D Sandra Milena Chingaté López searches for antimicrobial peptides –structures produced by the skin and nose, mouth and digestive system mucous membranes– which produce a barrier that thwarts infection. They prevent the growth of microbes and have lethal action against bacteria, fungi, and viruses. “The main antimicrobial peptides (AMPs) described are defensins, cathelicidins, and lactoferrin,” adds Chingaté.
One of the main results of her doctoral research is the discovery of cathelicidins, peptides LL-37 (human), PMAP-36 (swine) and CAP-18 (rabbits) as candidates for new molecules that work as anti-tuberculosis compounds.
The identification of AMPs started by modifying cathelicidins with help from bioinformatics software, searching for areas of these molecules having greater antimicrobial activity and producing a positive charge which could then link to negatively charged phospholipids of Mycobacterium tuberculosis membranes.
Dr. Chingaté, of the UNal Department of Chemistry Microbacterium Biochemistry and Molecular Biology Research Group, explained: “We obtained16 modified peptides with greater antibacterial potential and they also increased their positive charge maintaining a non-polar area that could serve as a counterbalance to the negative charge of bacteria membranes.”
During the experimental stage, AMPs were tested on two resistant strains of Mycobacterium smegmatis mc2155 and Mycobacterium tuberculosis H37Ra and they obtained a minimum improved inhibitory concentration of 2 to 6 times, meaning that APRs diminished the concentration of the antibiotic necessary to kill the bacteria.
Furthermore, transmission electron microscopy (a technique in which a beam of electrons is transmitted through a specimen to form a high-definition image) determined that peptides can breakdown bacteria. Likewise, through an enzymatic reaction, they discovered they were capable of interfering with the activity of ATPase enzymes, responsible for releasing high metal concentrations such as copper and zinc that work as bacteria contaminating agents.
“Once the bacteria enter the human body it activates defense mechanisms and when the bacillus is phagocyted or devoured by the macrophage, the body begins to produce a hostile environment and heightens the concentration of heavy metals such as copper and zinc, producing a toxic environment for the microbacterium, which tries to defend itself and becomes resistant to drugs,” said Chingaté.”
Other discoveries of the work of Dr. Chingaté are that cathelicidins peptides taken from humans, swine, and rabbits activate the immune response of the body to control the infection.
Also, if conventional antibiotics link to identified structures, they can boost their potential without causing negative effects on the cells of TB patients, i.e. without affecting red blood cells.
According to Chingaté, “Drugs made from peptides could be used that need a lower dose and that additionally do not have cytotoxic activities, in other words, that kill or damage “good” cells or tissue.”
Therefore, peptides derived from identified cathelicidins are an alternative to offset TB because they have a possible action mechanism different from first and second-line conventional antibiotics, as they are less invasive and have an action mechanism in which bacteria are unlikely to develop resistance.
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