Elsevier

Drug Discovery Today

Volume 26, Issue 1, January 2021, Pages 31-43
Drug Discovery Today

Review
Keynote
Novel approaches for the treatment of methicillin-resistant Staphylococcus aureus: Using nanoparticles to overcome multidrug resistance

https://doi.org/10.1016/j.drudis.2020.10.011Get rights and content

Highlights

  • Superbugs such as MRSA are highly prevalent infections with high mortality rates.

  • Biofilms and antibiotic resistance impede effective treatment of MRSA.

  • Conventional therapies are ineffective because of multiple resistance mechanisms in MRSA.

  • Targeted nanoparticles that can overcome biofilms and drug resistance hold great promise for successful MRSA treatment.

Methicillin-resistant Staphylococcus aureus (MRSA) causes serious infections in both community and hospital settings, with high mortality rates. Treatment of MRSA infections is challenging because of the rapidly evolving resistance mechanisms combined with the protective biofilms of S. aureus. Together, these characteristic resistance mechanisms continue to render conventional treatment modalities ineffective. The use of nanoformulations with unique modes of transport across bacterial membranes could be a useful strategy for disease-specific delivery. In this review, we summarize treatment approaches for MRSA, including novel techniques in nanoparticulate designing for better therapeutic outcomes; and facilitate an understanding that nanoparticulate delivery systems could be a robust approach in the successful treatment of MRSA.

Introduction

Staphylococcus aureus is a Gram-positive bacterium responsible for many complex infections, including skin and soft tissue, pneumonia, bone and joint infections, osteomyelitis, and infective endocarditis [1]. A high mortality rate resulting from S. aureus was observed when antibiotic treatments were not available [2]. Penicillin came into use as a treatment for these infections, but resistance developed to this antibiotic within 2 years. Soon, ∼80% of S. aureus were penicillin resistant [3]. Following this development, methicillin was introduced, with stability against degradation by the penicillinase enzyme. However, methicillin resistance began as soon as it was used to treat the infections [4] and became a major clinically relevant concern from 1960 onwards [5]. MRSA infection is acquired predominately in two settings: secondary to exposure in a healthcare facility, such as hospitals, nursing homes, or dialysis centers [termed health care-associated MRSA (HA-MRSA)]; or exposure acquired in otherwise healthy individuals in the community [termed community-associated MRSA (CA-MRSA)]. In 2017, the Center for Disease Control (CDC) recorded 323 700 cases and 10 600 deaths as ‘incident hospitalized positive clinical cultures, including hospital- & community-onset MRSA infections’ [6]. Chamber and DeLeo illustrated the trends of this resistance, which was first identified during the 1940s and is ongoing [3] (Fig. 1). The most recent wave of vancomycin resistance was first identified during the 2000s and remains prevalent. Although treatment of MRSA remains challenging, the much needed progress in MRSA infection management has slowed significantly [7].

Section snippets

Resistance mechanisms

Resistance to antimicrobial agents is a major reason for the failure of MRSA treatment. There are various mechanisms that contribute to antimicrobial resistance. These can be inherent to MRSA or acquired with the time and length of treatment. Each antibiotic combats MRSA by different mechanisms of action characteristic of the antibiotic class. Similarly, the subsequent resistance mechanisms against each of these drug classes in MRSA can also manifest by different mechanisms (Fig. 2). Table 1

Drawbacks of current conventional therapies

There are various treatment options available clinically for MRSA. Although vancomycin remains the frontline treatment option, it has several limitations, such as high dosage, longer treatment duration, renal toxicity, and low oral absorption, with intravenous injection, although inconvenient, the only available treatment method 31, 32. In addition to vancomycin, there are other drugs available on the market that could circumvent the drug resistance seen in MRSA therapy. However, when

Nanoparticles for the delivery of anti-MRSA agents

Given that current treatment strategies for MRSA are either rendered ineffective or have shown severe adverse effects, there is a need to find alternative strategies besides novel drug discovery and repurposing of current drugs. This alternative strategy could also contribute to improving the bioavailability and safety of current treatments. Research endeavors have been made in this direction to enhance the bioactivity and bioavailability of different pharmaceutical agents by using nanoparticle

Photodynamic therapy

The use of nontoxic dyes or photosensitizers (PS) in conjunction with harmless visible light, known as photodynamic therapy (PDT), has become popular [111] and can be used successfully to eradicate the growth of tumors. A similar strategy was used to suppress the growth of bacterial cells. Perni described the implementation of light-activated NPs to enhance the delivery of agents to the infection site [112].

Liposomes have been widely explored for PDT using hematoporphyrin to enhance activity

Challenges for nanodrug delivery for MRSA treatment

The success of any nanoparticulate treatment method depends on the ability of the formulation to translate to the clinical setting. However, there are many obstacles in the clinical translation of therapies to the clinic. The first is standardization of the in vitro analyses that are applied at every step of the development of a formulation. These include a variety of experimental methods, from the evaluation of MIC of an antibiotic to toxicity assays, biofilm imaging assays, and so on [120].

Prospects and applications of nanotechnology

A characteristic feature of nanotechnology is its ability to make existing products more efficient by introducing new functionality. Nanodrugs are now available in the clinic to treat various cancers, fungal infections, iron deficiency, and macular degeneration, have also been used as image contrast agents, vaccines, and anesthesia, and have successfully demonstrated greater efficacy compared with conventional models of therapy [126]. Increasing research, development, and translation of novel

Concluding remarks

MRSA treatment faces several challenges with limited therapeutic options. Although some drugs have been introduced to replace or work in synergy with the most widely used drugs, such as vancomycin, all have seen developing resistance by MRSA and, hence, increasing MIC values and dosage required. Moreover, these drugs are also associated with other adverse effects, such as renal toxicity and hepatotoxicity, in addition to their ineffectiveness against bacterial biofilms, which remain one of the

Acknowledgments

K.V. would like to acknowledge the Department of Pharmaceutical Sciences, Wayne State University for a Frank O Taylor scholarship. A.K.I. acknowledges the Michigan Translational Research and Commercialization (MTRAC) award (#380121), EACPHS FRAP award (#477482) and Wayne State University start-up award (#176575) for funding the MRSA projects in his lab.

Kushal Vanamala is pursuing a MSc in the Iyer lab in the Department of Pharmaceutical Sciences at Wayne State University (WSU). His current research focuses on developing targeted nanoparticle delivery systems for infectious diseases and cancers.

References (128)

  • N. Shaik

    Interactions of pluronic block copolymers on P-gp efflux activity: experience with HIV-1 protease inhibitors

    J. Pharm. Sci.

    (2008)
  • R. Pelgrift et al.

    Nanotechnology as a therapeutic tool to combat microbial resistance

    Adv. Drug Deliv Rev.

    (2013)
  • S. Chakraborty

    In vitro antimicrobial activity of nanoconjugated vancomycin against drug resistant Staphylococcus aureus

    Int. J. Pharm.

    (2012)
  • J. Lim

    Peptidoglycan binding protein (PGBP)-modified magnetic nanobeads for efficient magnetic capturing of Staphylococcus aureus associated with sepsis in blood

    Sci. Rep.

    (2019)
  • A. Pumerantz

    Preparation of liposomal vancomycin and intracellular killing of meticillin-resistant Staphylococcus aureus (MRSA)

    Int. J. Antimicrob. Agents.

    (2011)
  • A.J. Huh et al.

    ‘Nanoantibiotics’: a new paradigm for treating infectious diseases using nanomaterials in the antibiotics resistant era

    J. Control Release.

    (2011)
  • L.A. Garske

    Rifampicin and sodium fusidate reduces the frequency of methicillin-resistant Staphylococcus aureus (MRSA) isolation in adults with cystic fibrosis and chronic MRSA infection

    J. Hosp. Infect.

    (2004)
  • W.S. Wu

    Efficacy of combination oral antimicrobial agents against biofilm-embedded methicillin-resistant Staphylococcus aureus

    J. Microbiol. Immunol. Infect.

    (2013)
  • F. Esmaeili

    Preparation and antibacterial activity evaluation of rifampicin-loaded poly lactide-co-glycolide nanoparticles

    Nanomedicine

    (2007)
  • E. Cevher

    Characterization of biodegradable chitosan microspheres containing vancomycin and treatment of experimental osteomyelitis caused by methicillin-resistant Staphylococcus aureus with prepared microspheres

    Int. J. Pharm.

    (2006)
  • A. Nabikhan

    Synthesis of antimicrobial silver nanoparticles by callus and leaf extracts from saltmarsh plant, Sesuvium portulacastrum

    L. Colloids Surf. B Biointerfaces.

    (2010)
  • M. Guzman

    Synthesis and antibacterial activity of silver nanoparticles against gram-positive and gram-negative bacteria

    Nanomedicine

    (2012)
  • S.Y.C. Tong

    Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management

    Clin. Microbiol. Rev.

    (2015)
  • D. Skinner et al.

    Significance of bacteremia caused by Staphylococcus aureus

    Arch. Intern. Med.

    (1941)
  • H.F. Chambers et al.

    Waves of resistance: Staphylococcus aureus in the antibiotic era

    Nat. Rev Microbiol.

    (2009)
  • W. Brumfitt et al.

    Methicillin-resistant Staphylococcus aureus

    N. Engl. J. Med.

    (1989)
  • CDC

    Antibiotic Resistance Threats in the United States

    (2019)
  • D.J. Diekema

    Twenty-year trends in antimicrobial susceptibilities among Staphylococcus aureus from the SENTRY Antimicrobial Surveillance Program

    Open Forum Infect Dis.

    (2019)
  • W.C. Reygaert

    An overview of the antimicrobial resistance mechanisms of bacteria

    AIMS Microbiol.

    (2018)
  • M. Hirenkumar et al.

    Poly Lactic-co-glycolic acid (PLGA) as biodegradable controlled drug delivery carrier

    Polymers

    (2011)
  • D. Davies

    Understanding biofilm resistance to antibacterial agents

    Nat. Rev. Drug Discov.

    (2003)
  • M. Piechota

    Biofilm formation by methicillin-resistant and methicillin-sensitive Staphylococcus aureus strains from hospitalized patients in Poland

    Biomed. Res. Int.

    (2018)
  • K.M. Craft

    Methicillin-resistant: Staphylococcus aureus (MRSA): antibiotic-resistance and the biofilm phenotype

    MedChemComm

    (2019)
  • M.L. Hanke

    Targeting macrophage activation for the prevention and treatment of Staphylococcus aureus biofilm infections

    J. Immunol.

    (2013)
  • F. Günther

    MRSA decolonization failure-are biofilms the missing link?

    Antimicrob. Resist. Infect. Control

    (2017)
  • H.C. Flemming

    Biofilms: an emergent form of bacterial life

    Nat. Rev. Microbiol.

    (2016)
  • M. El-Azizi

    In vitro activity of vancomycin, quinupristin/dalfopristin, and linezolid against intact and disrupted biofilms of staphylococci

    Ann. Clin. Microbiol. Antimicrob.

    (2005)
  • L. Hall-Stoodley

    Bacterial biofilms: from the natural environment to infectious diseases

    Nat. Rev. Microbiol.

    (2004)
  • S. Miyaue

    Bacterial memory of persisters: Bacterial persister cells can retain their phenotype for days or weeks after withdrawal from colony-biofilm culture

    Front Microbiol.

    (2018)
  • Idexx

    Microbiology Guide to Interpreting Minimum Inhibitory Concentration

    (2019)
  • A.H. Salem

    Pharmacodynamic assessment of vancomycin-rifampicin combination against methicillin resistant Staphylococcus aureus biofilm: a parametric response surface analysis

    J. Pharm. Pharmacol.

    (2011)
  • I. Ojea-Jiménez

    Facile preparation of cationic gold nanoparticle-bioconjugates for cell penetration and nuclear targeting

    ACS Nano.

    (2012)
  • P.S. Stewart

    Daptomycin rapidly penetrates a Staphylococcus epidermidis biofilm

    Antimicrob. Agents Chemother.

    (2009)
  • R. Boudjemaa

    New insight into daptomycin bioavailability and localization in Staphylococcus aureus biofilms by dynamic fluorescence imaging

    Antimicrob. Agents Chemother.

    (2016)
  • J. Bauer

    A combined pharmacodynamic quantitative and qualitative model reveals the potent activity of daptomycin and delafloxacin against Staphylococcus aureus biofilms

    Antimicrob. Agents Chemother.

    (2013)
  • K.E. Barber

    A novel approach utilizing biofilm time-kill curves to assess the bactericidal activity of ceftaroline combinations against biofilm- producing methicillin-resistant Staphylococcus aureus

    Antimicrob. Agents Chemother.

    (2014)
  • K.L. LaPlante et al.

    Activities of daptomycin and vancomycin alone and in combination with rifampin and gentamicin against biofilm-forming methicillin-resistant Staphylococcus aureus isolates in an experimental model of endocarditis

    Antimicrob. Agents Chemother.

    (2009)
  • M.J. Rybak

    The pharmacokinetic and pharmacodynamic properties of vancomycin activity

    Clin. Infect. Dis.

    (2006)
  • S.T. Micek

    Alternatives to vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections

    Clin. Infect. Dis.

    (2007)
  • M. Bell

    Antibiotic misuse: a global crisis

    JAMA

    (2014)
  • Cited by (0)

    Kushal Vanamala is pursuing a MSc in the Iyer lab in the Department of Pharmaceutical Sciences at Wayne State University (WSU). His current research focuses on developing targeted nanoparticle delivery systems for infectious diseases and cancers.

    Marc Scheetz is a professor at Midwestern University in the Chicago College of Pharmacy and holds a joint appointment in the Department of Pharmacology, College of Graduate Studies. Dr Scheetz was awarded a Doctorate of Pharmacy from Butler University, earned a MSc in Clinical Investigation at Northwestern University, and completed his pharmacy practice residency and an infectious diseases fellowship at Northwestern Memorial Hospital. Dr Scheetz is also the Director of the Pharmacometric Center of Excellence at Midwestern University. He currently practices clinically as an infectious diseases pharmacist at Northwestern Memorial Hospital in Chicago, IL and serves as the Director for the Post-Doctoral Fellowship Program in Infectious Diseases Pharmacotherapy.

    Michael J. Rybak is a professor of pharmacy in the Department of Pharmacy Practice, adjunct professor of pharmaceutical sciences in, and Director of the Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy & Health Sciences, WSU. He is also adjunct Professor of Medicine, Division of Infectious Diseases, School of Medicine, WSU and adjunct Clinical Professor of Pharmacy, College of Pharmacy, University of Michigan. His research focus is antimicrobial pharmacokinetics and pharmacodynamics and the assessment of infectious diseases outcomes, including their relationship to bacterial resistance. His most recent work focuses on the use of combination therapy, including the use of bacteriophages plus antibiotics to prevent resistance.

    David Andes is the William Craig Professor in the Departments of Medicine and Medical Microbiology, Head of the Division of Infectious Diseases, and Director of the Wisconsin Antimicrobial Drug Discovery and Development Center. His research strives to identify strategies to combat antimicrobial drug resistance. His study tactics span from the bench to the clinic, including delineating the optimal dosing strategies for the treatment of drug-resistant infections, identifying new resistance mechanisms, discovering new antimicrobial drugs and targets, and clinical study of resistance epidemiology.

    Arun K. Iyer is an associate professor and the Director of the U-BiND Systems Laboratory at the Department of Pharmaceutical Sciences, WSU. Dr. Iyer received his PhD from Sojo University, Japan, under Hiroshi Maeda. In 2012, Dr. Iyer received the prestigious CRS T. Nagai Research Achievement Award. He has authored >100 publications in peer-reviewed international journals and books and has wide expertise in biomaterials and nanomedicine for treating diseases such as infection, dementia, and cancer.

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