Genomic identification of cryptic susceptibility to penicillins and β-lactamase inhibitors in methicillin-resistant Staphylococcus aureus

Abstract

Antibiotic resistance in bacterial pathogens threatens the future of modern medicine. One such resistant pathogen is methicillin-resistant Staphylococcus aureus (MRSA), which is resistant to nearly all β-lactam antibiotics, limiting treatment options. Here, we show that a significant proportion of MRSA isolates from different lineages, including the epidemic USA300 lineage, are susceptible to penicillins when used in combination with β-lactamase inhibitors such as clavulanic acid. Susceptibility is mediated by a combination of two different mutations in the mecA promoter region that lowers mecA-encoded penicillin binding protein 2a (PBP2a) expression, and in the majority of isolates by either one of two substitutions in PBP2a (E246G or M122I) that increase the affinity of PBP2a for penicillin in the presence of clavulanic acid. Treatment of S. aureus infections in wax moth and mouse models demonstrate that penicillin/β-lactamase inhibitor susceptibility can be exploited as an effective therapeutic choice for 'susceptible' MRSA infection. Finally, we show that isolates with the PBP2a E246G substitution have a growth advantage in the presence of penicillin, but the absence of clavulanic acid, which suggests that penicillin/βlactamase susceptibility is an example of collateral sensitivity (resistance to one antibiotic increases sensitivity to another). Our findings suggest that widely available and currently disregarded antibiotics could be effective in a significant proportion of MRSA infections.

Genomic diversity of prevalentStaphylococcus epidermidismultidrug-resistant strains isolated from a Children’s Hospital in México City in an eight-years survey

“…In the SE collection, only the S07 strain was susceptible to oxacillin (6 µg/ml) in plate assays, despite the detection of mecA in the genome. Altogether, these results indicate that most of the SE strains (15) studied here are MRSE, identified by the presence of the mecA gene; any phenotypic inconsistencies could be due to lack of expression of the mecA , heteroresistance, or the limitation of the current antibiotic susceptibility testing methods (Band et al., 2019; Harrison et al, 2019; Nicoloff et al, 2019).…”

Epidemiology, evolution and cryptic susceptibility of methicillin-resistant Staphylococcus aureus in China: a whole-genome-based survey

“…[6] A recent study used sequencing to identify cryptic susceptibility of MRSA to penicillins in combination with β-lactamase inhibitors in different lineages. [7] Susceptibility (as defined by an epidemiological cut-off) is due to two different mutations in J o u r n a l P r e -p r o o f the mecA promotor region that lower mecA expression, and in the majority of isolates, by either one of two additional substitutions in PBP2a that increases its affinity for penicillin in the presence of clavulanic acid.…”

Peer Review #3 of "Genomic diversity of prevalent Staphylococcus epidermidis multidrug-resistant strains isolated from a Children’s Hospital in México City in an eight-years survey (v0.4)"

“…In the SE collection, only the S07 strain was susceptible to oxacillin (6 g/ml) in plate assays, despite the detection of mecA in the genome. Altogether, these results indicate that most of the SE strains (15) studied here are MRSE, identified by the presence of the mecA gene; any phenotypic inconsistencies could be due to lack of expression of the mecA, heteroresistance, or the limitation of the current antibiotic susceptibility testing methods (Band et al 2019;Harrison et al 2019;Nicoloff et al 2019).…”