RISE proposal 2012


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RISE proposal 2012

  1. 1. Possible Substitute for Beta-lactamAntibiotics Through the Exploration of and make it inefficient in completing thePenicillin-binding proteins disruption of the cell wall synthesis. AlteredNicolle A. Rosa-Mercado, UPR Cayey PBPs found in bacteria can deform the bacteria’s shape. PBPs give the antibiotic theAbstract ability of preventing the formation of the Beta-lactam antibiotics are a common bacteria’s cell wall; they are specificallyremedy for most bacterial diseases, but involved in the last stages of peptidoglycanrecently it has been discovered that bacteria synthesis. Peptidoglycan is known to be theare able to develop a resistance to these major component in the bacteria’s cell wall.antibiotics through enzymes called beta- These proteins are classified according tolactamases. Beta-lactam antibiotics work by their molecular weight, for example, PBP1ainhibiting penicillin-binding proteins (PBPs), has a bigger molecular weight than PBP5.which are essential for cell wall synthesis, There may be more than one type ofbecause of a ring called the beta-lactam ring. penicillin-binding proteins found in a bacteriaBeta-lactamases break the ring open and or antibiotic.inhibit the antibiotic. It is of extreme Although PBPs may be a major threat toimportance to find a non-beta-lactam bacteria, the overproduction of PBPs causesantibiotic that has the same ability of antibiotic resistance in bacteria; also ainhibiting penicillin-binding proteins. formation of PBPs with low affinity forIntroduction penicillin, like PBP5, may create this resistance. Bacteria can also create resistance Penicillin-binding proteins are a big group to a beta-lactam antibiotic if they have beta-of proteins that are characterized by uniting to lactamase or the penicillinase enzymebeta-lactam antibiotics to reinforce the because it breaks the beta-lactam ring openantibiotic’s efficiency. Beta-lactam antibiotics making the antibiotic ineffective; this processare a broad group of antibiotics with a beta- is called the enzymatic hydrolysis of the beta-lactam nucleus in their molecular structure. lactam ring. The deactivation of someThis binding is possible because these penicillin-binding proteins in bacteria canproteins have similar chemical structure to lead to its death, meaning that some PBPs aresome components of peptidoglycan. essential for the bacteria’s life. An example ofPenicillin-binding proteins have the ability of bacteria that has a high level of resistance tomaking a beta-lactam antibiotic, such as beta-lactam antibiotics is Streptococcuspenicillin, efficient, but an altered PBP, as pneumoniae, which is Gram-positive. Thisthey are called, can weaken an antibiotic resistance however can be mediated by making several changes in the molecular
  2. 2. structure, and the location of some penicillin- In conclusion, penicillin-binding proteinsbinding proteins in the bacteria. Penicillin- can be both an advantage and a disadvantagebinding proteins are essential to all antibiotics for bacteria because, in the absence of anand are a threat to all bacteria. antibiotic, they complete the bacterial cell wall, but in the presence of a beta-lactamHypothesis and Objectives antibiotic, they may be used to destroy the The hypothesis for this investigation would bacteria itself. A non-beta-lactam antibioticbe that antibiotics that have a similar structure which kills bacteria through the manipulationto beta-lactams might be used to substitute of PBPs would be extremely beneficial due tothem in bacteria that have developed a the fact that the bacteria would not be able toresistance to beta-lactams. To do this, the become resistant to it through the use of beta-antibiotic must be able to bind with a lactamase.penicillin-binding protein so it can destroy the References:bacterial cell wall. The objective of thisproposal is to find a non-beta-lactam •http://www.ncbi.nlm.nih.gov/pmc/articles/antibiotic so that the bacteria is not able to PMC192226/create a resistance to it through beta- •Herzberg O., Moult J. (1987) BActeriallactamase. Resistance to Beta-Lactam Antibiotics:Methodology and Expected Results Crystal Structure of Beta-lactamases from Staphylococcus aureus PC1 at 2.5A The methodology would consist of Resolution. Science/ AAAS Vol.236 no.4802selecting non-beta-lactam antibiotics that Pp.694-701behave similarly to beta-lactams at amolecular level. The selected antibiotics •Basu J., Chattopadhyay R., Kundu M., andwould be inserted into an Escherichia coli Chakrabarti P. (1992) Purification and partialcolony, a Gram-negative bacteria, and a characterization of a penicillin bindingStreptococcus pneumoniae colony, a Gram- protein from Mycobacterium smegmatis.positive bacteria, to observe which prove to American Society for Microbiology – Journalbe effective and which do not. Depending on of Bacteriology. Vol. 174, No. 14 pp. 4829–the previous results, the relation between the 4832non-beta-lactam antibiotic and the penicillinbinding protein would be studied. Theexpected conclusions for this experimentwould be to find a non-beta-lactam antibioticthat is able to effectively kill bacteria throughpenicillin-binding proteins.