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Abstract(s)
A descoberta da penicilina e, o desenvolvimento e implementação da plataforma de Waksman promoveu a época dourada da decoberta de antibióticos, de 1930 a 1970, após a qual a descoberta de novas classes abrandou consideravelmente. O uso generalizado de antibióticos e a escassez de novas classes de fármacos com atividade antimicrobiana culminaram no aparecimento e disseminação global de estirpes bacterianas multirresistentes com impacto em saúde pública, resultando em 4,95 milhões de mortes associadas à resistência aos antibióticos em 2019, assim como uma perda estimada de até 5% do PIB global até 2050 devido a custos de saúde e perda de produtividade.
Vários mecanismos de resistência ao longo dos anos têm contribuído para a redução da eficácia dos antibióticos, sendo os associados aos β-lactâmicos especialmente importantes devido à importância e espetro de atividade deste grupo. A produção de β-lactamases de gram-negativos como a Klebsiella pneumoniae ou a produção de PBPs alternativas por parte de Staphylococcus aureus resistantes à meticilina (MRSA) são mecanismos extremamente importantes pela sua prevalência e impacto e cujo conhecimento é fulcral na implementação de novas estratégias terapêuticas, de controlo da infeção e descoberta de novos fármacos.
Importa também destacar que a lista de agentes patogénicos prioritários associados à resistência está a aumentar. Recentemente atualizada, esta lista compilada pela Organização Mundial de Saúde destaca a relevância de espécies como o Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacteriaceae e MRSA que demonstraram uma combinação de vários mecanismos que, em diversas situações, tornam virtualmente impossível a instituição de um regime terapêutico eficaz. Porém, esta dissertação realça e foca-se sobretudo em espécies bacterianas passíveis de serem consideradas enquanto ameaças emergentes, agentes patogénicos que, apesar de ainda haver tratamento disponível, possuem múltiplas resistências intrínsecas ou uma extensa taxa de incidência. Este trabalho, destaca assim a relevância e pertinência da notificação e desenvolvimento de estratégias que possam limitar a propagação de Burkholderia pseudomallei, Stenotrophomonas maltophilia, ou Campylobacter jejuni.
Também o Mycobacterium tuberculosis resistente à rifampicina é abordado dada a sua recente classificação enquanto agente de prioridade crítica e para o qual se observa um aumento crescente no número de resistências acumuladas.
The discovery of penicillin and the development and adoption of the Waksman platform drove a period known as the golden age of antibiotic discovery from 1930 to 1970, after which antibiotic discovery of new classes slowed down considerably. The widespread use of antibiotics and the lack of new classes of drugs with antimicrobial activity culminated in the emergence and the global dissemination of multidrug resistant bacterial strains with impact on public health, resulting in 4.95 million deaths associated with antibiotic resistance in 2019, as well as an estimated loss of up to 5% of global GDP until 2050 due to healthcare costs and loss of productivity. Several resistance mechanisms have contributed to the reduction of antibiotic effectiveness over the years, with β lactam associated ones being especially important due to the importance and large spectrum of activity of this group. β-lactamase production in gram-negative bacteria such as Klebsiella pneumoniae or alternative PBP production in methicillin resistant Staphylococcus aureus (MRSA) are extremely important mechanisms due to their prevalence and impact and whose understanding is pivotal in the implementation of new therapeutic strategies, infection control and, drug discovery. Its also important to point out that the priority pathogens associated with resistance list is growing. Recently updated, this list compiled by the World Health Organization highlights the relevance of species such as Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacteriaceae and MRSA that have shown a combination of several mechanisms that in several situtations have turned them virtually impossible the establishment of an effective therapeutic regimen. However, this dissertation highlights and focuses especially on bacterial species capable of being considered emerging threats, pathogens that while there is still available treatment possess multiple intrinsic resistances or a widespread incidence rate. This work thus underlines the relevance and pertinence of the notification and development of strategies that might limit propagation of resistant strains of Burkholderia pseudomallei, Stenotrophomonas maltophilia and Campylobacter jejuni. Rifampicin resistant Mycobacterium tuberculosis is also aproached due to its recent classification as a critical priority agent and for which an increasing trend in the number of accumulated resistances can be observed.
The discovery of penicillin and the development and adoption of the Waksman platform drove a period known as the golden age of antibiotic discovery from 1930 to 1970, after which antibiotic discovery of new classes slowed down considerably. The widespread use of antibiotics and the lack of new classes of drugs with antimicrobial activity culminated in the emergence and the global dissemination of multidrug resistant bacterial strains with impact on public health, resulting in 4.95 million deaths associated with antibiotic resistance in 2019, as well as an estimated loss of up to 5% of global GDP until 2050 due to healthcare costs and loss of productivity. Several resistance mechanisms have contributed to the reduction of antibiotic effectiveness over the years, with β lactam associated ones being especially important due to the importance and large spectrum of activity of this group. β-lactamase production in gram-negative bacteria such as Klebsiella pneumoniae or alternative PBP production in methicillin resistant Staphylococcus aureus (MRSA) are extremely important mechanisms due to their prevalence and impact and whose understanding is pivotal in the implementation of new therapeutic strategies, infection control and, drug discovery. Its also important to point out that the priority pathogens associated with resistance list is growing. Recently updated, this list compiled by the World Health Organization highlights the relevance of species such as Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacteriaceae and MRSA that have shown a combination of several mechanisms that in several situtations have turned them virtually impossible the establishment of an effective therapeutic regimen. However, this dissertation highlights and focuses especially on bacterial species capable of being considered emerging threats, pathogens that while there is still available treatment possess multiple intrinsic resistances or a widespread incidence rate. This work thus underlines the relevance and pertinence of the notification and development of strategies that might limit propagation of resistant strains of Burkholderia pseudomallei, Stenotrophomonas maltophilia and Campylobacter jejuni. Rifampicin resistant Mycobacterium tuberculosis is also aproached due to its recent classification as a critical priority agent and for which an increasing trend in the number of accumulated resistances can be observed.
Description
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2024, Universidade de Lisboa, Faculdade de Farmácia
Keywords
Multidrug resistant bacteria Emerging threats Resistance mechanisms Mestrado Integrado - 2024