2019-08-25

Pharmacology

The field of pharmacology has evolved enormously since its introduction to science. It is a scientific sector that originally described the explicit effects of biologically active substances. Currently, the discipline focuses on the molecular mechanisms by which drugs exert biological effects. Looking it at the broader perspective, pharmacology is a scientific discipline that studies effects of chemical agents both natural and synthetic have on biological systems. This includes the research on chemical properties, derivatives, physiological and behavioral effects, biological transformations, and mechanisms of actions, therapeutic and non-therapeutic applications of the drug. Pharmacological research may determine the chemical agent’s effects on subcellular, physiological, systemic and behavioral processes. It also concentrates on treatment and prevention of illnesses or the possible dangers pesticide and herbicides pose. The following discussion will look at the importance of computer software in the discovery of new antibiotics in the fight against antimicrobial resistance.

Humimycins

Most antibiotics in the current market are based on the metabolites produced by bacteria. However, most bacteria have mutated their molecular systems to become resistance to most available antibiotics increasing the need to search for new effective antibiotics. Looking for new antibiotics has not been a simple task because sometimes it means discovering new bacteria producing active biological agents or coaxing the already known bacteria to produce new metabolites with therapeutic properties. Nonetheless, scientists have discovered ways to counteract these problems (Rockefeller University).

One of the approaches they have used is using computational tactics to determine the genes in the genome of bacteria involved in the synthesis of biologically active molecules. After identification of these genes, they can then use the information to synthesize the molecules themselves rather than using microorganisms. Using this approach scientists in Rockefeller University were able to produce two promising new antibiotics without necessarily cultural a single bacterium as required by conventional methods.

Sean Brady head of Genetically Encoded Small Molecules Laboratory led a team that started searching publicly available databases for possible bacterial genomes that inhabited the human body. They then applied specialized computer programs to filter hundreds of such genomes for groups of genes with potential ability to synthesize metabolites referred to as non-ribosomal peptides that act as precursors of most antibiotics (John et al.).They also applied the computer programs to predict molecule chemical structures that these gene groups ought to produce.

Identifying the Humimycins

The computer software first identified 57 possible useful gene groups, which scientists filtered down to 30. Brady and his fellow scientists the employed another approach referred to as solid-phase peptide synthesis to produce 25 different chemical agents. They then tested these chemical compounds against bacteria causing diseases to human beings and successfully found that two related compounds which they named humimycin A and humimycin B (John et al.). These molecules are found bacteria family known as Rhodococcus, microorganisms that had not produced anything similar to humimycins before when cultured using conventional laboratory methods.

Humimycins showed effectiveness against the streptococcus and staphylococcus bacteria, dangerous human’s pathogens that have caused several human diseases in the past and have produced resistance to the current antibiotics. They conducted further experiments to determine the molecular mechanism trough which these compounds exert their effects. The experiment suggested that these compounds function by inhibiting an enzyme that participates in the synthesis of cell walls of these microbes and once the production of the cell wall is interfered with bacteria die (John et al.). This is a similar mode used by the beta-lactam antibiotics, an array of drugs typically administered for the treatment of bacterial infections and whose efficacy fades away as bacteria establish new mechanisms for drug resistance. Another amazing finding they noticed is the ability of humimycin to re-sensitive the bacteria to the beta-lactam antibiotics that were previously not effective against them.

Synergistic functions

In another experiment Brady and his compatriots used humimycins in combination with beta-lactams against the notorious staphylococcus bacteria that are resistant to beta-lactam and they noticed increased efficacy than when humimycin is used alone. The increased efficiency was as result of these compounds interference with two different phases in the same biochemical pathway (John et al.). To confirm this result Brady and his group exposed a rat to antibiotic resistance microbe called staphylococcus aureus, a bacteria that frequently leads diseases characterized by drug resistance in hospital patients. They then divided the mice into three groups and used three sets of drugs each for the treatment of each group. The first regimen consisted of a combination of beta-lactam and humimycin and the others had were made up a single of either drug. The group of mice that received the mixture of drugs fared far much better compared to those treated with a single drug. This outcome could pave a way of coming up with the regimen for treatment of diseases caused by beta-lactam resistant S. aureus.

Anti-efflux compounds  

In another study, Helen Zgurskaya, a professor of biochemistry and chemistry at OU College of Arts and Sciences and her crew of scientists identified four news DE Novo molecules that look for and destroy bacteria proteins referred to as efflux pumps, a molecular majorly involved in resistance if antibiotics by microbes. Like Brady and his group, they also applied computer software but this time to scan for several drugs target and to the screen of likely active compounds rapidly (University of Oklahoma website). To achieve this, they used a supercomputer called ORNL. They combined information from this computer with the experiments to look for the molecules that were working well. This is important as it dramatically reduces the required time to move from experimental step to clinical trials. In the initial screening, they took only twenty minutes using about 42000 processors, and they obtained several promising outcomes (Narges et al.,). After an extensive analysis, they narrowed down the list to predict molecules with higher potential of causing disruption to the bacterial wall envelope.

The group concentrated on an efflux protein called AcrA that joins two other proteins to form a tunnel through the bacterial cell wall. It is a tunnel used by bacteria to get rid of antibiotic compounds in the cytoplasm (Narges et al.,). So destroying this pump could basically break the efflux pump increasing the efficacy of other antibiotics. The OU scientists conducted lab experiment to confirm the function of the identified molecules in disruption of efflux pump whereas the synthesis of structural analogs was performed by SLU School of Medicine research crew

Conclusion

These findings could be a starting point for scientists to harvest bacterial genomes found in online databases that could be useful in producing several other molecules that might prove crucial in the fight against antibiotics resistance by S. aureus. Similar approached could also be used finding products that could work against May other bacterial species that lie above human microbiome, and that might store their own molecular treasures. This is very exciting considering the fact that most bacteria genomes have not been mapped. Thus there is great potential in this particular area of pharmacology.

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