Academic journal article Genetics

A Fitness Cost Associated with the Antibiotic Resistance Enzyme SME-1 ß-Lactamase

Academic journal article Genetics

A Fitness Cost Associated with the Antibiotic Resistance Enzyme SME-1 ß-Lactamase

Article excerpt

ABSTRACT

The bla^sub TEM-1^ β-lactamase gene has become widespread due to the selective pressure of β-lactam use and its stable maintenance on transferable DNA elements. In contrast, bla^sub SME-1^ is rarely isolated and is confined to the chromosome of carbapenem-resistant Serratia marcescens strains. Dissemination of bla^sub SME-1^ via transfer to a mobile DNA element could hinder the use of carbapenems. In this study, bla^sub SME-1^ was determined to impart a fitness cost upon Escherichia coli in multiple genetic contexts and assays. Genetic screens and designed SME-1 mutants were utilized to identify the source of this fitness cost. These experiments established that the SME-1 protein was required for the fitness cost but also that the enzyme activity of SME-1 was not associated with the fitness cost. The genetic screens suggested that the SME-1 signal sequence was involved in the fitness cost. Consistent with these findings, exchange of the SME-1 signal sequence for the TEM-1 signal sequence alleviated the fitness cost while replacing the TEM-1 signal sequence with the SME-1 signal sequence imparted a fitness cost to TEM-1 β-lactamase.Taken together, these results suggest that fitness costs associated with some β-lactamases may limit their dissemination.

HORIZONTAL gene transfer must overcome several barriers before stable maintenance of the transferred gene in the recipient bacteria can occur. DNA entry, avoidance of restriction systems, and incorporation into the host replication machinery are necessary steps for transfer (Thomas and Nielsen 2005). Although fulfilling these criteria permits a gene to transfer, the gene must also confer a selective advantage to expand within the bacterial population (Berg and Kurland 2002). Such is the case with the rapid dissemination of b-lactamase genes in response to the selective pressure of b-lactam use. A better understanding of the barriers to horizontal gene transfer and possible costs associated with maintenance of the transferred gene may facilitate the development of strategies to reduce the spread of antibiotic resistance.

b-Lactamases provide bacterial resistance to b-lactam antibiotics by catalyzing the hydrolysis of these drugs. The widespread dissemination of b-lactamase genes represents an ongoing challenge to the efficacy of treatment with b-lactam antibiotics. A large collection of b-lactamases exists and can be classified into four groups (A-D) on the basis of primary amino acid sequence homologies (Ambler 1980). The most prevalent plasmid-borne b-lactamase in Enterobacteriaceae is the class A TEM-1 b-lactamase (Shah et al. 2004). The spread of this b-lactamase to >25 species of gramnegative bacteria has contributed to increased bacterial resistance to penicillins and early cephalosporins and thereby has reduced their efficacy as anti-bacterial agents. In response to increased bacterial resistance to these b-lactams, extended spectrum cephalosporins and b-lactamase inhibitors were introduced in the 1980s. The selective pressure resulting from the introduction of these antibiotics has resulted in the rapid evolution of TEM-1 b-lactamase. There are now > 100 TEM-1 variants containing amino acid substitutions that allow the enzyme to hydrolyze extended-spectrum b-lactams and/or avoid inactivation by the b-lactamase inhibitors (http://www.lahey.org). To date, no TEM-1 variants capable of conferring resistance to a third class of b-lactams, the carbapenems, have surfaced.

Carbapenem resistance is often associated with decreased cell-wall permeability and the presence of class B or class D b-lactamases that are distantly related to the class A b-lactamase TEM-1 (Navon-Venezia et al. 2005). A few class A b-lactamases capable of hydrolyzing carbapenems (referred to as carbapenemases) have been discovered in clinical Enterobacteriaceae isolates. One such carbapenemase, SME-1, has been identified in several Serratia marcescens strains and is encoded by the chromosomal blaSME-1 gene (Yanget al. …

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