Abstract
Multidrug-resistant bacteria arise mostly by the accumulation of plasmids and chromosomal mutations. Typically, these resistant determinants are costly to the bacterial cell. Yet, recently, it has been found that, in Escherichia coli bacterial cells, a mutation conferring resistance to an antibiotic can be advantageous to the bacterial cell if another antibiotic-resistance mutation is already present, a phenomenon called sign epistasis. Here we study the interaction between antibiotic-resistance chromosomal mutations and conjugative (i.e., self-transmissible) plasmids and find many cases of sign epistasis (40%)—including one of reciprocal sign epistasis where the strain carrying both resistance determinants is fitter than the two strains carrying only one of the determinants. This implies that the acquisition of an additional resistance plasmid or of a resistance mutation often increases the fitness of a bacterial strain already resistant to antibiotics. We further show that there is an overall antagonistic interaction between mutations and plasmids (52%). These results further complicate expectations of resistance reversal by interdiction of antibiotic use.
Highlights
Multidrug resistance is a major hurdle for modern medicine, putting at risk commonplace medical practices [1] and the treatment of infection by bacterial pathogens [2]
Bacteria can become resistant to antibiotics by spontaneous mutation of chromosomal genes or through the acquisition of horizontally mobile genetic elements, mainly conjugative plasmids
Plasmid-borne resistance is widespread among bacterial pathogens
Summary
Multidrug resistance is a major hurdle for modern medicine, putting at risk commonplace medical practices [1] and the treatment of infection by bacterial pathogens [2]. In the absence of antibiotics, resistance mutations are often deleterious and confer a fitness cost to the cell [3,4,5,6]. It is logical to expect that, in the absence of antibiotic selective pressure, resistant strains will be outcompeted by the susceptible ones. A possible procedure to eliminate resistance is to ban the use of an antibiotic. This policy has been applied in different countries with varying results. A deliberate reduction in the prescription of macrolides in Finland, resulted in a 50% decrease in the frequency of macrolide-resistant group A streptococci [7]. Compensatory mutations even increase the level of resistance itself [14,15]
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