#penincillin

hese bacteria are responsible of diseases, such as meningitis, pneumonia, sinusitis and otitis. Researchers of the UNC discovered that the pneumococci which circulate in Argentina have a mechanism which facilitates the spread of the stumps resistant to penicillin. With the finding, the interest of infectious disease specialists, epidemiologists and the pharmaceutical industry it is open the possibility of designing the most effective antibiotics to fight the infections caused by these bacteria.

Streptococcus pneumoniae in spinal fluid. Center for Disease Control and Prevention / Dr. M.S. Mitchell.

Pneumococci are bacteria which are usually present in the nose and the pharynx, especially in children. They can originate different respiratory infections, such as pneumonia and meningitis as well as unchain otitis and sinusitis. They are generally treated with antibiotics called beta-lactam, among which penicillin is the most used. When the antibiotic is effective to treat the diseases caused by pneumococci it is said that the stump is sensitive to penicillin. On the contrary, if the treatment is not effective it is said that the stump is resistant to this antimicrobial. Both types of pneumococci live in the nose and pharynx “competing between themselves to establish an infection in the same biological niche”. International studies describe that sensitive pneumococci have a greater growth capacity than the resistant ones when no antibiotics are taken. But once the antimicrobial is introduced the sensitive stump dies and leaves place to the resistant to cause an infection. Alerted by the increase of resistant stumps in the central region of Argentina in the last decade, a team of researchers of the School of Chemical Sciences belonging to the Center for Research in Clinical Biochemistry and Immunology (Cibici) and directed by José Echenique, studied pneumococci stumps resistant to penicillin which circulate in en Argentina. Before, this group of scientists had made an epidemiological study using 200 pathogenic pneumococci stumps. This work was carried out in the frame of a program in epidemiology in which there participated Pediatric hospitals from Córdoba and other provinces, which included children younger than 5 years old. The key moment: cellular division The infections caused by pneumococci are generally treated with penicillin or other antibiotics of the family of beta-lactams. To attack the infection, penicillin has to be united to proteins involved in the cellular division of pneumococci, called PBP (Penicillin-Binding Proteins). So that this link is effective, it is crucial that it occurs during the bacteria’s growth. In this process there can be mistakes or mutations in DNA duplication. If these mutations are produced in the exact point in which penicillin acts, that is, in the genes associated to PBP’s to which penicillin is linked the bacterium becomes resistant. In this way, the antibiotic stops being effective to kill the bacterium. “We simulate the evolutionary process of bacteria by means of the progressive incorporation of mutations which contribute resistance to penicillin. We did it with microbiological techniques and then we analyzed the samples with molecular and cellular biology methods” indicated to InfoUniversidades Echenique. In order to understand better the behavior of the resistant stumps the researchers took sensitive stumps and incorporated to them genes (DNA) associated to PBP’s coming from resistant stumps, but instead of introducing the three genes together they added them one by one to see what was the individual behavior of each mutation regarding growth and resistance. The scientists discovered that individually each mutating gene grew less than when they were all together. This meant that the bacteria accumulated evolutionarily those mutations which were complemented between themselves to compensate the growth capacity and that at the same time gave them resistance. With complementary studies they proved that in the absence of antibiotics both stumps (sensitive and resistant) grew at the same levels. These results contradicted the things described in similar studies developed by specialists in the United States and Europe, according to which in the absence of antibiotics the resistant stumps grew less than those susceptible to penicillin. Then there were made new experiments in which they compared the genes of the resistant stumps which circulate in those countries with the ones we have in Argentina. “We took each gene, sequenced it and compared them with those of other countries and all the differences were evident. The stumps are resistant notwithstanding the level of resistance, but the mutations are very different”, indicates Echenique. “The circulating pneumococci stumps in Argentina have a mechanism which facilitates the spreading of stumps resistant to penicillin”, he concludes. Relevance of the results The increase in pneumococci stumps resistant to penicillin which circulate in the central region of Argentina could be explained by the overuse of antibiotics, as some specialists support. However, Echenique points out that in various countries the amount of antibiotics used decreased, especially beta-lactams, and however, “the rate of resistant stumps remained constant or grew slightly”. According to the researcher there might exist factors which collaborate in the spread of the resistant stumps and “the molecular mechanism we discovered is one of them, at least in the group of the pneumococci studied in Argentina”, he ensures. Besides, during the study of this mechanism they identified proteins which interacted with the PBP’s which hadn’t been studied up to that moment in pneumococci, “proteins also involved in the process of cellular division of these bacteria”. The finding which showed that up to the moment of cellular division the bacterium not only selects the mutations which contribute resistance, but also those which are compensated to offer it a greater level of growth, added to the discovery that they intervene in this process proteins not studied before, will permit the pharmaceutical industry to orient the research and design of antibiotics which “block the cellular division with the aim of obtaining more efficient antimicrobials to fight the stumps resistant to antibiotics”, says Echenique. It will also be useful for epidemiologists and infectious diseases’ specialists, as it permits to understand the cause of the high occurrence of resistant stumps. Translated to an everyday language this means that there might be more effective antibiotics to fight the infections which affect more frequently little children, especially those who go to school at a very early age. The results of this research were published in the journal “Plos Pathogens”, the most important scientific publication in the area of Microbiology in February, 2011.