Epistatic control of intrinsic resistance by virulence genes in Listeria

Abstract

Elucidating the relationships between antimicrobial resistance and virulence is key to understanding the evolution and population dynamics of resistant pathogens. Here, we show that the susceptibility of the gram-positive bacterium Listeria monocytogenes to the antibiotic fosfomycin is a complex trait involving interactions between resistance and virulence genes and the environment. We found that a FosX enzyme encoded in the listerial core genome confers intrinsic fosfomycin resistance to both pathogenic and non-pathogenic Listeria spp. However, in the genomic context of the pathogenic L. monocytogenes, FosX-mediated resistance is epistatically suppressed by two members of the PrfA virulence regulon, hpt and prfA, which upon activation by host signals induce increased fosfomycin influx into the bacterial cell. Consequently, in infection conditions, most L. monocytogenes isolates become susceptible to fosfomycin despite possessing a gene that confers high-level resistance to the drug. Our study establishes the molecular basis of an epistatic interaction between virulence and resistance genes controlling bacterial susceptibility to an antibiotic. The reported findings provide the rationale for the introduction of fosfomycin in the treatment of Listeria infections even though these bacteria are intrinsically resistant to the antibiotic in vitro.

Whole‐genome sequencing reveals Listeria monocytogenes diversity and allows identification of long‐term persistent strains in Brazil

“…2B) exhibited a C(187)T mutation in the fosX gene (resistance to fosfomycin). This new mutation results in a premature stop codon (PMSC) at residue 63, likely resulting in complete susceptibility to fosfomycin (Scortti et al, 2018). Acquired antibiotic resistance traits were not detected, with the exception of aacA4 (resistance to aminoglycosides) present in one isolate (isolate CLIST 2083, L1-SL3-ST3-CT4444).…”

Complexities in understanding antimicrobial resistance across domesticated animal, human, and environmental systems

“…Further, metagenomics methods cannot be easily used to link the presence of an ARG to a specific ARB, which can only be done stochastically in most scenarios. Finally, whether an ARG detected by metagenomics is present in viable bacteria, is sited alone in a genome or is part of a multidrug‐resistance cassette (e.g., on a plasmid) are facts not easily determined from metagenomics data alone . Such problems can be partially resolved by parallel culturing of organisms (from the same source as the metagenomics data), selection of specific phenotypes, and determining the genetic context of specific genes in such isolates.…”

“…Finally, whether an ARG detected by metagenomics is present in viable bacteria, is sited alone in a genome or is part of a multidrug-resistance cassette (e.g., on a plasmid) are facts not easily determined from metagenomics data alone. 4,95 Such problems can be partially resolved by parallel culturing of organisms (from the same source as the metagenomics data), selection of specific phenotypes, and determining the genetic context of specific genes in such isolates. However, the majority of organisms found in environmental systems cannot be cultured under standard laboratory conditions, which poses a problem for linking ARB and ARG metagenomics data within environmental compartments.…”

The inactivation of enzymes belonging to the central carbon metabolism, a novel mechanism of developing antibiotic resistance

“…Our results highlight the importance that the modification of the activity of enzymes belonging to central metabolism may have in the susceptibility to antibiotics, as fosfomycin, that are not known to interact with such enzymes. The finding that fosfomycin activity is highly dependent on the bacterial metabolic status, being more active when bacteria grow intracellularly (27, 28) or under acidic conditions and anaerobiosis in urine (62), further support that antibiotic activity and, consequently antibiotic resistance, are interlinked with the bacterial metabolism.…”

“…The main cause of this impaired uptake is the selection of mutations in any of the genes encoding the sugar phosphate transporters GlpT and UhpT, which are the gates for fosfomycin entrance (25, 26). To note here that expression of these transporters is under metabolic control, in such a way that situations where the nutritional bacterial status favors the use of sugar phosphates (as intracellular growth) increase fosfomycin activity (27, 28). Finally, in other cases, fosfomycin is inactivated by fosfomycin modifying enzymes as FosA, FosB and FosX.…”