Considerations and Caveats in Combating ESKAPE Pathogens against Nosocomial Infections

Abstract

ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are among the most common opportunistic pathogens in nosocomial infections. ESKAPE pathogens distinguish themselves from normal ones by developing a high level of antibiotic resistance that involves multiple mechanisms. Contemporary therapeutic strategies which are potential options in combating ESKAPE bacteria need further investigation. Herein, a broad overview of the antimicrobial research on ESKAPE pathogens over the past five years is provided with prospective clinical applications.

Keywords: antimicrobial peptides; antiresistance; antivirulence; bacteriophages; nanodelivery strategies.

Figure 1

Impact of antimicrobial resistance. Two teams from Europe modeled the increase in the rates of antimicrobial resistance (AMR) based on the information available in 2014, each using their own methodology, to understand the impact of AMR would have on the world population and its economic output. A) Deaths attributable to AMR every year compared to other major causes of death. The estimated number of AMR will increase to 10 million by 2050, approaching the total number of deaths caused by all diseases today. B) Deaths attributable to AMR in different parts of the world by 2050. There is a tendency for reduced mortality continents with better economic conditions and more stringent antibiotic management. C) The impact of AMR on the world's economy between 2014 and 2050 (in trillions of US dollars) predicts an exponentially loss in gross domestic product (GDP) attributable to combating AMR. Reproduced under the terms of the Creative Commons Attribution 4.0 International Public License.8 Copyright 2016, Review on Antimicrobial Resistance.

Figure 2

Ambler classification of β‐lactamases. A) Class A (extended spectrum), C (AmpC enzymes), and D (oxacillinase family): serine β‐lactamases‐mediated inactivation involves the attack of a nucleophilic serine. B) Class B (metallo): β‐lactam inactivation mediated by metallo‐β‐lactamases is facilitated by a nucleophilic attack via an activated water molecule coordinated to zinc ions. Reproduced with permission.103 Copyright 2010, Royal Society of Chemistry.

Figure 3

Quorum‐sensing inhibition and antivirulence strategies. A) Quorum‐sensing and inhibition mechanisms in Gram‐positive bacteria, using S. aureus as a model pathogen. B) Quorum‐sensing and inhibition mechanisms in Gram‐negative bacteria, using P. aeruginosa as a model pathogen. Synthases and exporters (dark blue) produce autoinducers that signal through receptors (gray). Activated receptors modulate gene expression of many virulence factors. Quorum‐sensing inhibitors can block ligand binding, promote receptor degradation, or block promoter binding. Quorum‐sensing feedback loops and crosstalk between pathways are omitted for simplicity. Reproduced with permission.127 Copyright 2017, Springer Nature. C) Summary of the targets of contemporary antivirulence strategies against Gram‐negative bacteria. These targets include (i) classical virulence factors such as adhesins/invasins, (ii) pathogen‐induced host signaling disruption by toxins, effectors, and immune modulators, (iii) microbial signal transduction and regulation, (iv) functions required for bacterial survival/persistence during infection. Reproduced with permission.156 Copyright 2015, Springer Nature.

Figure 4

Antimicrobial peptides (AMPs). A) Mechanisms of action of antimicrobial peptides. Reproduced with permission.177 Copyright 2017, Elsevier. B) Comparison between the antimicrobial mechanism(s) of (i) typical membrane‐disrupting cationic AMPs and (ii) structurally nanoengineered antimicrobial peptide polymers (SNAPPs) against Gram‐negative bacteria. Reproduced with permission.226 Copyright 2016, Springer Nature.

Figure 5

Nanodelivery strategies. A) General structure of a liposome. Reproduced with permission.297 Copyright 2014, Elsevier. B) Proposed killing mechanisms and summary of disruption of P. aeruginosa biofilms by farnesol‐ and ciprofloxacin‐loaded liposomes. Reproduced with permission.301 Copyright 2016, ACS Publications (further permissions related to the material excerpted should be directed to the ACS).

Figure 6

Different strategies of using bacteriophages to combat pathogens. CRISPR: clustered regularly interspaced short palindromic repeats; Cas genes: CRISPR‐associated genes. Reproduced with permission.351 Copyright 2016, Springer Nature.

Figure 7

Modes of action: antibiotic versus photodynamic therapy (PDT). A) Different antibiotics (AB) react selectively with different molecules on specific organelles/structures. B) Nonspecific localization of a photosensitizer prior to illumination of the bacteria. Generation of reactive oxygen species (ROS) after light activation of the photosensitizer. Reproduced under a Creative Commons Attribution 3.0 Unported Licence.389 Copyright 2015, Published by The Royal Society of Chemistry (RSC) on behalf of the European Society for Photobiology, the European Photochemistry Association, and RSC. C) Schematic representation of antimicrobial PDT. Reproduced with permission.393 Copyright 2015, Elsevier.

Figure 8

Antibiotics and strategies against multidrug‐resistant bacteria in the past 20 years. Humans are belittled and vulnerable in their confrontation with the expanding galaxies of multidrug‐resistant bacteria. Introduction of a new antibacterial agent was soon followed by a corresponding sophisticated bacteria resistant strategy which renders the drug nonfunctional against the new resistant strains. AMP: antimicrobial peptide; CDC: Center for Disease Control & Prevention; MDR: multidrug‐resistant; N. gonorrhoeae: Neisseria gonorrhoeae; NDM‐1: New Delhi metallo‐beta‐lactamase 1; PDR: pan drug‐resistant; WHO: World Health Organization; XDR: extensively drug‐resistant. *CDC guidelines for the prevention of perinatal Group B Stretococcal diseases; **Collaboration between pharmaceutical companies and national/international policy‐making bodies.