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Understanding antibiotic resistance via outer membrane permeability

Authors Ghai I, Ghai S

Received 14 November 2017

Accepted for publication 21 December 2017

Published 11 April 2018 Volume 2018:11 Pages 523—530

DOI https://doi.org/10.2147/IDR.S156995

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Joachim Wink

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Ishan Ghai,1,2 Shashank Ghai3

1School of Engineering and Life Sciences, Jacobs University, Bremen, Germany; 2Consultation Division, RSGBIOGEN, New Delhi, India; 3Leibniz University Hannover, Hannover, Germany

Abstract: Collective antibiotic drug resistance is a global threat, especially with respect to Gram-negative bacteria. The low permeability of the bacterial outer cell wall has been identified as a challenging barrier that prevents a sufficient antibiotic effect to be attained at low doses of the antibiotic. The Gram-negative bacterial cell envelope comprises an outer membrane that delimits the periplasm from the exterior milieu. The crucial mechanisms of antibiotic entry via outer membrane includes general diffusion porins (Omps) responsible for hydrophilic antibiotics and lipid-mediated pathway for hydrophobic antibiotics. The protein and lipid arrangements of the outer membrane have had a strong impact on the understanding of bacteria and their resistance to many types of antibiotics. Thus, one of the current challenges is effective interpretation at the molecular basis of the outer membrane permeability. This review attempts to develop a state of knowledge pertinent to Omps and their effective role in solute influx. Moreover, it aims toward further understanding and exploration of prospects to improve our knowledge of physicochemical limitations that direct the translocation of antibiotics via bacterial outer membrane.

Keywords: antibiotics, Gram-negative bacteria, drug-resistance, outer membrane proteins, porins, membrane permeability, influx

 

Introduction

At the end of the 20th century, the attention of the scientific as well as the pharmaceutical community regarding the threat of antibiotic resistance was mainly focused on multiresistant Gram-positive bacteria.1,2 This significantly contributed towards the development of new compounds with the specific activity against this particular group of microorganisms.1 Regrettably, the introduction of antibiotics for Gram-negative bacteria has not developed at a similar pace.1 Gram-negative bacterial multidrug resistance is a worrying health issue. Antibiotic resistance is frequently reported in clinical Gram-negative bacteria, and severely limits the available therapeutic options in hospital acquired infections.2,3 Consequently, due to the shortage of novel active antibacterials, there is an immense need to interpret the molecular mechanisms of antibiotic resistance, especially toward key Gram-negative clinical pathogens, such as Klebsiella, Enterobacter, Pseudomonas, Campylobacter, Acinetobacter, and Salmonella species.48

The current innovative mode of improving the potential of antibiotics is to efficiently introduce them into the bacteria and further prevent them from degradation by bacterial enzymes before they reach their targets.7,8 This is, however, an extreme method for countering the problem of antibiotic resistance.9,10 The main mechanisms employed by Gram-negative bacteria against available antibiotic therapy include the enzymatic barrier, which primarily destroys the antibiotics; the membrane barrier, which limits the intracellular access of antibiotics; and antibiotic target modification, resulting in the overall failure of antibiotic therapy.7 Significantly, these mechanisms can work together in clinical isolates, thus creating an elevated level of antibiotic resistance.4,6,8 Of these mechanisms, antibiotic infusion across the bacterial membranes11 is one of the crucial mechanisms that needs to be studied thoroughly.59 Passing over toward the outer membrane barricade to scope the inhibitory concentration inside the bacterial cell is a key step for antibiotic molecules to work effectively,11 thus, understanding the mechanism of transport across the outer membrane will give a crucial insight towards designing futuristic “smart” antibiotics.7,8,10 The outer membrane of Gram-negative bacteria performs the crucial role of providing an extra layer of protection to the organism without conceding the exchange of material required for sustaining life. In this dual capacity, this barrier appears to be an extremely sophisticated macromolecular assemblage, the complexity of which has been explored only in recent years.5,8,1215 By combining a highly hydrophobic lipid bilayer containing pore-forming proteins (Omps) (Tables 1 and 2) of specific size-exclusion properties, the outer membrane acts as a selective barricade.7,8 The permeability properties of this barrier, therefore, have a major impact on the susceptibility of the microorganism to antibiotics. Small hydrophilic drugs, such as β-lactams, use the pore-forming porins to gain access to the cell interior, while macrolides and other hydrophobic drugs diffuse across the lipid bilayer.4,12,13 The existence of drug-resistant strains in many bacterial species due to modifications in the lipid or protein composition of the outer membrane indeed highlights the importance of the outer membrane barrier in antibiotic sensitivity. For instance, any structural changes in the available outer membrane proteins can significantly account for antibiotic resistance.5 Further, the situation becomes serious when the permeability barrier synchronizes with the β-lactamases in the periplasmic space, potentially leading to third-generation cephalosporin resistance.47 In Gram-negative bacteria, the outer membrane is an asymmetric bilayer of phospholipid and lipopolysaccharides (LPS), with the latter exclusively found in the outer leaflet.4,5 A typical LPS molecule consists of three parts, together with a relatively short core oligosaccharide, lipid A, a glucosamine-based phospholipid, and a distal polysaccharide O-antigen.12 Since part of the core oligosaccharide and the O-antigen are not required for the growth of Escherichia coli, strains can exhibit varying lengths of these structures.4,5,12,13 The phospholipid composition of the inner leaflet of the outer membrane contains approximately 15% phosphatidylglycerol, 80% phosphatidylethanolamine, and 5% cardiolipin, like that of the cytoplasmic membrane.12 Many different types of proteins reside in the outer membrane (Table 1). Some of them are extremely abundant. Different outer membrane proteins have been characterized in Gram-negative bacteria (Table 2) and are distinguished according to their substrate specificities, functional structure (monomeric or trimeric), and their regulation and expression.46,12,13

Table 1 Crucial Omps studied in different bacteria

Note: Copyright ©2017. Dove Medical Press. Adapted from Ghai I, Ghai S. Exploring bacterial outer membrane barrier to combat bad bugs. Infect Drug Resist. 2017;10:261–273.8

Table 2 Conclusive investigations with different Omps studied in pathogens

Note: Copyright ©2017. Dove Medical Press. Adapted from Ghai I, Ghai S. Exploring bacterial outer membrane barrier to combat bad bugs. Infect Drug Resist. 2017;10:261–273.8

Abbreviations: LSA, liposome swelling assay; LPS, lipopolysaccharides; MS, molecular simulations; ETP, electrophysiology.

In this present review, we discuss and tabulate different attributes to understand various outer membrane proteins mainly responsible for solute influx in Gram-negative bacteria.4,10 This active knowledge can be used towards understanding the effect of outer membrane influx in antibiotic resistance in Gram-negative bacteria which can be further used for future antibiotic drug development.

Conclusion

In this review, we continued to explore different outer membrane proteins by extending and recapitulating the progressive systematic evidence elucidating the role of Omps in solute membrane permeability in Gram-negative bacteria.7,8 Bacterial membrane transport is a multifaceted process that is strongly controlled by a complicated network of activities that sense and respond to external stress.8 Significantly, bacteria make use of these cultured controlled cascades that perceive and distinguish different toxic compounds and respond by triggering various resistance mechanisms, including modification of specific Omps.46,13,122 Membrane penetrability, which further, along with added resistance mechanisms, including drug inactivation or target modification, has become one of the major problems in effective antibiotic therapy. Effective information regarding the role of effective Omps in substrate uptake and further explaining their structural relationship toward the uptake, highlights the capability of the scientific community in the direction of understanding the bacterial resistance machinery generated mainly via modification of membrane permeability.48,13,122 Understanding translocation via Omps can be regarded as a first step toward defining a pathway of an antibiotic specific to its target. Consequently, interpretation of antibiotic translocation through Omps is crucial for understanding the connection between influx and activities in bacteria. The function of the general diffusion Omp has been well studied based on Omp characteristics, alteration, and mutations. We also tried to combine data from different studies concerning the Omps. Our understanding of the structure of the pore-forming complex has been extremely improved over the last decade with emergence of the computational approach, crystallographic data from X-rays, electron microscopy, mass spectrometry, and electrophysiology. However, significant key knowledge regarding the transformation of outer membrane pores’ transportation mechanism is still required to further elaborate their conditional role in antibiotic/antimicrobial transport. The molecular basis of antibiotic transport via specific porins is presently open to interpretation, and additional rigorous studies are required to give insight into the structural–activity relationship between Omp geometry and antibiotic transport. Collectively, the current and previous8 data can be employed in an effort to explain substrates, especially antibiotic uptake pathways, and may provide insights into molecular mechanisms that could enable rational drug design to enhance permeation and provide novel strategies to solve the “impermeability” issue of antibiotic resistance.

Acknowledgments

The publication of this article was funded by the Open Access fund of Leibniz Universität Hannover. The authors sincerely thank their research groups for their support.

Disclosure

The authors report no conflicts of interest in this work.

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