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An Alanine Permease Mutation Or Exposure to D-Cycloserine Increases the Susceptibility Of bioRxiv preprint doi: https://doi.org/10.1101/616920; this version posted June 22, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 An alanine permease mutation or exposure to D-cycloserine increases the susceptibility of 2 MRSA to -lactam antibiotics 3 4 Laura A. Gallagher1, Rebecca K. Shears2, Claire Fingleton1, Laura Alvarez3, Elaine M. 5 Waters1,2, Jenny Clarke2, Laura Bricio-Moreno2, Christopher Campbell1, Akhilesh K. Yadav3, 6 Fareha Razvi4, Eoghan O'Neill5, Alex J. O’Neill6, Felipe Cava3, Paul D. Fey4, Aras Kadioglu2 and 7 James P. O’Gara1* 8 9 1School of Natural Sciences, National University of Ireland, Galway, Ireland. 10 2Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and 11 Global Health, University of Liverpool, UK. 12 3MIMS-Molecular Infection Medicine Sweden, Molecular Biology Department, Umeå 13 University, Umeå, Sweden. 14 4Department of Pathology and Microbiology, University of Nebraska Medical Center, 15 Omaha, Nebraska, USA. 16 5Department of Clinical Microbiology, Royal College of Surgeons in Ireland, Connolly 17 Hospital, Dublin 15, Ireland. 18 6Antimicrobial Research Centre, School of Molecular and Cellular Biology, Faculty of 19 Biological Sciences, University of Leeds, Leeds, UK. 20 21 22 23 *Correspondence: [email protected] 24 25 Running title: Re-sensitization of AMR pathogens to -lactams 26 27 1 bioRxiv preprint doi: https://doi.org/10.1101/616920; this version posted June 22, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 28 Abstract. Prolonging the clinical effectiveness of β-lactams, which remain first-line 29 antibiotics for many infections, is an important part of efforts to address antimicrobial 30 resistance. We report here that inactivation of the predicted D-cycloserine (DCS) transporter 31 gene cycA re-sensitizes MRSA to β-lactam antibiotics. The cycA mutation also resulted in 32 hyper-susceptibility to DCS, an alanine analogue antibiotic that inhibits the alanine 33 racemase and D-alanine ligase enzymes required for D-alanine incorporation into 34 peptidoglycan. Amino acid transport studies showed that CycA functions as an alanine 35 permease, and that impaired alanine transport in the cycA mutant correlated with increased 36 susceptibility to oxacillin and DCS. The cycA mutation was accompanied by increased 37 accumulation of muropeptides with tripeptide stems lacking the terminal D-ala-D-ala, and 38 reduced peptidoglycan cross linking. Exposure of MRSA to DCS was also associated with a 39 dose-dependent accumulation of muropeptides with tripeptide stems and reduced PG 40 crosslinking. Because impaired alanine transport or DCS-treatment have similar effects on 41 PG structure, synergism between β-lactams and DCS was investigated. DCS re-sensitised 42 MRSA to β-lactam antibiotics in vitro and significantly enhanced MRSA eradication by 43 oxacillin in a mouse bacteraemia model. The susceptibility of several other ESKAPE group 44 pathogens to β-lactams was also increased by DCS. These data reveal that impaired uptake 45 of alanine or DCS-meditated inhibition of D-alanine incorporation into peptidoglycan 46 increases the susceptibility of MRSA to β-lactam antibiotics. 47 48 Importance. Treatment options for infections caused by ESKAPE group pathogens continue 49 to dwindle with increasing antimicrobial resistance. Particularly important are the β- 50 lactams, which remain first line antibiotics for many infections, and finding new ways to 51 maintain their clinical effectiveness is a priority. Here we report that impaired alanine 52 transport in an MRSA cycA mutant was associated with hyper-susceptibility to β-lactam 53 antibiotics and D-cycloserine (DCS). DCS, which is used in the treatment of multi-drug 54 resistant tuberculosis infections, re-sensitised MRSA to oxacillin and other β-lactams in vitro 55 and significantly enhanced oxacillin activity in a mouse model of bacteraemia. DCS also 56 sensitised other ESKAPE pathogens to β-lactams. These findings reveal important roles for 57 alanine transport and the pathway for D-alanine incorporation into peptidoglycan in 58 controlling the susceptibility of MRSA to β-lactam antibiotics. 2 bioRxiv preprint doi: https://doi.org/10.1101/616920; this version posted June 22, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 59 Introduction 60 Whilst many bacteria can exhibit resistance to select antimicrobials, isolates of the human 61 pathogen Staphylococcus aureus can express resistance to all licensed anti-staphylococcal 62 drugs. This results in significant morbidity and mortality, with up to 20% of patients with 63 systemic methicillin resistant S. aureus (MRSA) infections dying, despite receiving treatment 64 with anti-staphylococcal drugs (1). Although aggressive hospital infection prevention and 65 control initiatives appear to be having a positive impact on hospital-acquired MRSA rates in 66 developed countries, S. aureus infections caused by community-associated MRSA strains 67 and strains that are currently methicillin susceptible remain stubbornly high (2),(3). 68 As part of our efforts to identify improved therapeutic approaches for MRSA infections, we 69 recently described the novel use of -lactam antibiotics to attenuate the virulence of MRSA- 70 induced invasive pneumonia and sepsis (4). We demonstrated that oxacillin-induced 71 repression of the Agr quorum-sensing system and altered cell wall architecture resulted in 72 downregulated toxin production and increased MRSA killing by phagocytic cells, respectively 73 (4). Supporting this in vitro data, a randomised controlled trial involving 60 patients showed 74 that the -lactam antibiotic flucloxacillin in combination with vancomycin shortened the 75 duration of MRSA bacteraemia from 3 days to 1.9 days (5, 6). 76 Because expression of methicillin resistance in S. aureus impacts fitness and virulence and is 77 a regulated phenotype, further therapeutic interventions may also be possible. The 78 complexity of the methicillin resistance phenotype is evident among clinical isolates of 79 MRSA, which express either low-level, heterogeneous (HeR) or homogeneous, high-level 80 methicillin resistance (HoR) (7-9). Exposure of HeR isolates to-lactam antibiotics induces 81 expression of mecA, which encodes the alternative penicillin binding protein 2a (PBP2a) and 82 can select for mutations in auxiliary genes resulting in a HoR phenotype, including mutations 83 that affect the stringent response and c-di-AMP signalling (10-14). Because auxiliary genes 84 can influence the expression of methicillin resistance in MRSA, targeting the pathways 85 associated with such genes may identify new ways to increase the susceptibility of MRSA to 86 β-lactams. To pursue this, we performed a forward genetic screen to identify loci that 87 impact the expression of resistance to β-lactam antibiotics in MRSA. Using the Nebraska 88 Transposon Mutant Library, which comprises 1,952 sequence-defined transposon insertion 89 mutants (15), inactivation of an amino acid permease gene was found to reduce resistance 90 to cefoxitin, the β-lactam drug recommended by the Clinical and Laboratory Standards 3 bioRxiv preprint doi: https://doi.org/10.1101/616920; this version posted June 22, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 91 Institute for measuring mecA-mediated methicillin resistance in MRSA isolates. Impaired 92 alanine transport in the permease mutant also correlated with hyper-susceptibility to D- 93 cycloserine (DCS), an alanine analogue antibiotic that interferes with two enzymatic steps in 94 the D-alanine pathway of peptidoglycan biosynthesis. DCS exposure was shown to increase 95 the susceptibility of MRSA and other ESKAPE pathogens to β-lactam antibiotics. 96 Peptidoglycan analysis revealed that the cycA mutation or exposure to DCS results in loss of 97 the terminal D-ala-D-ala from the stem peptide and reduced cross-linking of the cell wall. 98 Given that β-lactam antibiotics remain among the most effective, safe and affordable 99 antibiotics, DCS deserves further consideration as a potential agent to restore the 100 therapeutic efficacy of -lactam antibiotics. 4 bioRxiv preprint doi: https://doi.org/10.1101/616920; this version posted June 22, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 101 Results 102 Mutation of cycA increases the susceptibility of MRSA to β-lactam antibiotics. To identify 103 new ways of controlling expression of methicillin resistance, we sought to identify novel 104 mutations involved in this phenotype. To achieve this, an unbiased screen of the Nebraska 105 Transposon
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