A computational model of antibiotic-resistance mechanisms in Methicillin-Resistant Staphylococcus aureus (MRSA)

Murphy, James T.; Walshe, Ray; Devocelle, Marc

doi:10.1016/j.jtbi.2008.05.037

Cited by 31 publications

(25 citation statements)

References 34 publications

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“…Staphylococcus pseudintermedius is occasionally isolated from serious human infections, and the emergence and spread of both meticillin‐resistant S. pseudintermedius (MRSP) strains and meticillin‐resistant Staphylococcus aureus (MRSA) are major veterinary and public health issues 8 . Meticillin resistance is of particular relevance because it is conferred by the presence of the mecA gene, which encodes for production of an altered penicillin binding protein (PBP2a) with a low affinity for all β‐lactam antimicrobials 9–11 . The emergence and dissemination of antimicrobial resistance amongst staphylococci is an important problem in human and veterinary medicine 1,8,11,12 .…”

Section: Introductionmentioning

confidence: 99%

In vitro susceptibility testing of meticillin‐resistant and meticillin‐susceptible staphylococci to mupirocin and novobiocin

Fulham

Lemarie

Hosgood

et al. 2010

Veterinary Dermatology

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Antimicrobials effective against meticillin-resistant staphylococci are limited. Mupirocin is a topical antimicrobial used to treat bacterial skin infections. Novobiocin is an oral antimicrobial approved for treatment of staphylococcal upper respiratory infections in dogs. This study reports the in vitro activity of mupirocin and novobiocin on meticillin-susceptible (MSS) and resistant staphylococci (MRS) from healthy dogs and dogs with superficial pyoderma. Staphylococci were isolated from skin swabs at four sites on healthy dogs and from lesions on dogs with superficial pyoderma. Staphylococci were identified by morphology and by catalase and coagulase testing. Speciation and susceptibility testing were performed by the Dade Microscan (W. Sacramento, CA, USA). Meticillin resistance was confirmed by an oxacillin screen plate. Novobiocin and mupirocin susceptibilities were tested by disc diffusion. Staphylococci were cultured from 61 healthy dogs (17 MRS and 44 MSS) and 30 dogs with pyoderma (15 MRS and 15 MSS), with higher proportions of MRS isolates in dogs with pyoderma (P=0.038; χ(2) test). For mupirocin, 79.5% (35 of 44) MSS and 82.3% (14 of 17) MRS isolates from healthy dogs, and 100% (15 of 15) MSS and 86.6% (13 of 15) MRS isolates from dogs with pyoderma were susceptible (MSS, P=0.094; MRS, P=1.0; Fisher's exact test). For novobiocin, 95.4% (42 of 44) MSS and 52.9% (nine of 17) MRS isolates from healthy dogs and 93.3% (14 of 15) MSS and 80% (12 of 15) MRS isolates from dogs with pyoderma were susceptible (MSS, P=1.0; MRS, P=0.148; Fisher's exact test).

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Section: Introductionmentioning

confidence: 99%

In vitro susceptibility testing of meticillin‐resistant and meticillin‐susceptible staphylococci to mupirocin and novobiocin

Fulham

Lemarie

Hosgood

et al. 2010

Veterinary Dermatology

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“…Another key component of methicillin-resistant mechanism is an acquired penicillin-binding protein (PBP), PBP-2′, which has unusually low affinity for all β -lactam antibiotics and most other antibiotics [88]. We have elucidated the distinctive structural features of PBP-2′ protein which can be exploited as chemotherapeutic targets for MSRA.…”

Section: Discussionmentioning

confidence: 99%

Identification of Functional Regulatory Residues of theβ-Lactam Inducible Penicillin Binding Protein in Methicillin-ResistantStaphylococcus aureus

Mbah

Isokpehi

2013

Chemotherapy Research and Practice

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Resistance to methicillin by Staphylococcus aureus is a persistent clinical problem worldwide. A mechanism for resistance has been proposed in which methicillin resistant Staphylococcus aureus (MRSA) isolates acquired a new protein called β-lactam inducible penicillin binding protein (PBP-2′). The PBP-2′ functions by substituting other penicillin binding proteins which have been inhibited by β-lactam antibiotics. Presently, there is no structural and regulatory information on PBP-2′ protein. We conducted a complete structural and functional regulatory analysis of PBP-2′ protein. Our analysis revealed that the PBP-2′ is very stable with more hydrophilic amino acids expressing antigenic sites. PBP-2′ has three striking regulatory points constituted by first penicillin binding site at Ser25, second penicillin binding site at Ser405, and finally a single metallic ligand binding site at Glu657 which binds to Zn2+ ions. This report highlights structural features of PBP-2′ that can serve as targets for developing new chemotherapeutic agents and conducting site direct mutagenesis experiments.

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“…To explore the effect of these processes, explicitly tracking local epidemiological dynamics across a continuous spatial gradient (as in Smith et al, 2004 andDébarre et al, 2009), as well as approaches based on pair approximations (e.g.,. Sato, Matsuda, & Sasaki, 1994;Levin & Durrett, 1996;Bolker & Pacala, 1997) or even spatially explicit, agent-based stochastic simulations and cellular automata (e.g., Hotchkiss, Strike, Simonson, Broccard, & Crooke, 2005;Murphy, Walshe, & Devocelle, 2008), may complement the patch-occupancy-based models we have proposed here to studying the spatial spread of antimicrobial resistance. Such detailed, stochastic simulations are needed to assess how implementing some of the strategies we explore (e.g., restraining migration or altering the global fitness costs) are likely to slow the spread of antimicrobial resistance in space under more realistic conditions.…”

Section: Models Inmentioning

confidence: 95%

Managing the emergence of pathogen resistance via spatially targeted antimicrobial use

Okamoto

Post

Vasseur

et al. 2018

Evolutionary Applications

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From agriculture to public health to civil engineering, managing antimicrobial resistance presents a considerable challenge. The dynamics underlying resistance evolution reflect inherently spatial processes. Resistant pathogen strains increase in frequency when a strain that emerges in one locale can spread and replace pathogen subpopulations formerly sensitive to the antimicrobial agent. Moreover, the strength of selection for antimicrobial resistance is in part governed by the extent of antimicrobial use. Thus, altering how antimicrobials are used across a landscape can potentially shift the spatial context governing the dynamics of antimicrobial resistance and provide a potent management tool. Here, we model how the efficacy of adjusting antimicrobial use over space to manage antimicrobial resistance is mediated by competition among pathogen strains and the topology of pathogen metapopulations. For several pathogen migration scenarios, we derive critical thresholds for the spatial extent of antimicrobial use below which resistance cannot emerge, and relate these thresholds to (a) the ability to eradicate antimicrobial‐sensitive pathogens locally and (b) the strength of the trade‐off between resistance ability and competitive performance where antimicrobial use is absent. We find that in metapopulations where patches differ in connectedness, constraining antimicrobial use across space to mitigate resistance evolution only works if the migration of the resistant pathogen is modest; yet, this situation is reversed if the resistant strain has a high colonization rate, with variably connected metapopulations exhibiting less sensitivity to reducing antimicrobial use across space. Furthermore, when pathogens are alternately exposed to sites with and without the antimicrobial, bottlenecking resistant strains through sites without an antimicrobial is only likely to be effective under a strong competition–resistance trade‐off. We therefore identify life‐history constraints that are likely to suggest which pathogens can most effectively be controlled by a spatially targeted antimicrobial regime. We discuss implications of our results for managing and thinking about antimicrobial resistance evolution in spatially heterogeneous contexts.

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A computational model of antibiotic-resistance mechanisms in Methicillin-Resistant Staphylococcus aureus (MRSA)

Cited by 31 publications

References 34 publications

In vitro susceptibility testing of meticillin‐resistant and meticillin‐susceptible staphylococci to mupirocin and novobiocin

In vitro susceptibility testing of meticillin‐resistant and meticillin‐susceptible staphylococci to mupirocin and novobiocin

Identification of Functional Regulatory Residues of theβ-Lactam Inducible Penicillin Binding Protein in Methicillin-ResistantStaphylococcus aureus

Managing the emergence of pathogen resistance via spatially targeted antimicrobial use

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