Biochimie & Pharmacologie : Libre accès
Libre accès

Abstrait

Sequential Responses of Bacteria to Noxious Agents (Antibiotics) Leading To Accumulation of Mutations and Permanent Resistance

Ana Martins, Gabriella Spengler, Joseph Molnar and Leonard Amaral

Bacteria have the capacity, as all living cells, to escape harm from a noxious agent by extruding the agent before it reaches its target and harms to the cell. This initial response is intrinsic and involves plasma membrane bound efflux pumps which have the capacity to recognise and extrude a large variety of structurally unrelated molecules. When the concentration of the agent is progressively increased, the number of efflux pumps is also progressively increased as a consequence of over-expression of genes that regulate and code for the synthesis of these pumps. Often, when the bacterium is transferred to drug free medium, the number of pump units returns to baseline levels. However, when the concentration of agent is maintained over a prolonged period of time, mutations in genes that code for essential proteins which are usual targets of antibiotics, begin to accumulate and the expression of genes that code for the efflux pumps decreases, oftentimes reaching wild type levels. When the patient is treated with an antibiotic over a prolonged period of time and initial therapy is ineffective, the bacterium most likely escapes via its own intrinsic efflux pump system and with time, it is expected that the number of efflux pump units progressively increase rendering the clinical isolate resistant to the given antibiotic. The amount of energy needed to maintain a high level of efflux pump activity is great and at the expense of other activities that are needed for survival and replication. When this point is reached, and following the second law of thermodynamics, the bacterium goes through changes to survive at low energy costs (for example: switches its mutator gene and a number of predicted mutations of essential proteins take place). These changes render the bacterium permanently resistant to given antibiotics, the need for efflux is no longer and the number of efflux pump units returns to baseline levels. This review will discuss the structure, genetic regulation, physiology of efflux pumps and the means by which a clinical isolate can be characterized for the components that contribute to its resistance during therapy, namely, evaluation of efflux pump activity versus mutations. The ability of a laboratory to perform these evaluations will go a long way toward the selection of effective antibiotic therapy on a real-basis.