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Non-Essential Targets in the Development of Antibiotics and Enhancers of Antimicrobial Therapy

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 76571

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Special Issue Editors

Dr. Barbara Campanini

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Guest Editor

Laboratory of Biochemistry and Molecular Biology, Food and Drug Department, University of Parma, 43124 Parma, Italy
Interests: PLP-dependent enzymes; cysteine biosynthesis; protein–protein interaction; conditionally essential targets in pathogens; hemophores

Dr. Marco Pieroni

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Guest Editor

Food and Drug Department, University of Parma, Parma, Italy
Interests: drug discovery; medicinal chemistry; antibacterials; antituberculars
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Special Issue Information

Dear Colleagues,

Recent years have seen the increasing incidence of antimicrobial resistance in widespread pathogens such as Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii and the Enterobacteriaceae, with the development of multidrug resistant and extensively drug resistant phenotypes. These bacteria, grouped under the acronym ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species), represent the leading cause of nosocomial infections worldwide. Currently, resistance is affecting all antibiotic classes, including the most recently marketed ones such as penems, quinolones and oxazolidindiones. Indeed, the acquistion of resistance is a natural trait of bacteria and it is part of their ability to adapt and evolve in challenging environments.

To tackle antibacterial resistance, either slight chemical modifications of a given molecule, keeping its pharmacophore intact, and/or whole-cell biological screening of compound libraries have been usually carried out. These approaches have in general prevailed over a target-based drug design due to the low rate of success of the latter procedure. For instance, the penetration of molecules through the cell wall, especially in Gram-negative bacteria, represents the most common pitfall that has halted delevopment of otherwise very potent in vitro inhibitors. Nonetheless, “non-essential targets“ have caught the attention of researchers, since they potentially represent a source of unexploited mechanisms that, in principle, tackle bacterial virulence and fitness without directly affecting cell viability, thereby decreasing the selection pressure for resistance to arise. Non-essential targets are, by definition, targets that are dispensable for bacterial growth in vitro and in rich medium, but which may be conditionally important for e.g., invasion or persistance in the host. Targeting proteins and enzymes that are non-essential should, in principle, disarm the pathogen and enable a sustained immune response to clear the infection. However, the conditional essentiality of these targets makes their identification difficult, and to gain adequate insight often requires a multidisciplinary approach, exploiting a combination of biochemistry, molecular biology, microbiology and medicinal chemistry.

Improving our knowledge of well-characterised, virulence-associated targets and finding new conditionally-essential targets in metabolic pathways will lead to a better understanding of the interplay between host and pathogen and will facilitate the discovery of new molecules for the enhancement of antibiotic therapy. In this Special Issue, we aim to assemble some of the more recent insights into non-essential target identification, validation and inhibition.

Dr. Barbara Campanini
Dr. Marco Pieroni
Guest Editors

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Keywords

Antibiotic resistance
Non-essential targets
Conditionally essential targets
Antibiotic adjuvant therapies
Target-based drug discovery
Virulence factors
Combination therapy
Host-directed therapy

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Published Papers (10 papers)

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Research

Jump to: Review

16 pages, 2595 KiB

Open AccessArticle

2-Aminopyridine Analogs Inhibit Both Enzymes of the Glyoxylate Shunt in Pseudomonas aeruginosa

by Alyssa C. McVey, Sean Bartlett, Mahmud Kajbaf, Annalisa Pellacani, Viviana Gatta, Päivi Tammela, David R. Spring and Martin Welch

Int. J. Mol. Sci. 2020, 21(7), 2490; https://doi.org/10.3390/ijms21072490 - 3 Apr 2020

Cited by 4 | Viewed by 2884

Abstract

Pseudomonas aeruginosa is an opportunistic pathogen responsible for many hospital-acquired infections. P. aeruginosa can thrive in diverse infection scenarios by rewiring its central metabolism. An example of this is the production of biomass from C₂ nutrient sources such as acetate via the glyoxylate shunt when glucose is not available. The glyoxylate shunt is comprised of two enzymes, isocitrate lyase (ICL) and malate synthase G (MS), and flux through the shunt is essential for the survival of the organism in mammalian systems. In this study, we characterized the mode of action and cytotoxicity of structural analogs of 2-aminopyridines, which have been identified by earlier work as being inhibitory to both shunt enzymes. Two of these analogs were able to inhibit ICL and MS in vitro and prevented growth of P. aeruginosa on acetate (indicating cell permeability). Moreover, the compounds exerted negligible cytotoxicity against three human cell lines and showed promising in vitro drug metabolism and safety profiles. Isothermal titration calorimetry was used to confirm binding of one of the analogs to ICL and MS, and the mode of enzyme inhibition was determined. Our data suggest that these 2-aminopyridine analogs have potential as anti-pseudomonal agents. Full article

(This article belongs to the Special Issue Non-Essential Targets in the Development of Antibiotics and Enhancers of Antimicrobial Therapy)

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8 pages, 1320 KiB

Open AccessArticle

Evaluation of Thio- and Seleno-Acetamides Bearing Benzenesulfonamide as Inhibitor of Carbonic Anhydrases from Different Pathogenic Bacteria

by Andrea Angeli, Mariana Pinteala, Stelian S. Maier, Bogdan C. Simionescu, Andrea Milaneschi, Ghulam Abbas, Sonia del Prete, Clemente Capasso, Antonella Capperucci, Damiano Tanini, Fabrizio Carta and Claudiu T. Supuran

Int. J. Mol. Sci. 2020, 21(2), 598; https://doi.org/10.3390/ijms21020598 - 17 Jan 2020

Cited by 20 | Viewed by 2823

Abstract

A series of 2-thio- and 2-seleno-acetamides bearing the benzenesulfonamide moiety were evaluated as Carbonic Anhydrase (CA, EC 4.2.1.1) inhibitors against different pathogenic bacteria such as the Vibrio cholerae (VchCA-α and VchCA-β), Burkholderia pseudomallei (BpsCA-β and BpsCA-γ), Mycobacterium tuberculosis (Rv3723-β) and the Salmonella enterica serovar Typhimurium (StCA2-β). The molecules represent interesting leads worth developing as innovative antibacterial agents since they possess new mechanism of action and isoform selectivity preferentially against the bacterial expressed CAs. The identification of potent and selective inhibitors of bacterial CAs may lead to tools also useful for deciphering the physiological role(s) of such proteins. Full article

(This article belongs to the Special Issue Non-Essential Targets in the Development of Antibiotics and Enhancers of Antimicrobial Therapy)

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21 pages, 4505 KiB

Open AccessArticle

Combination of SAXS and Protein Painting Discloses the Three-Dimensional Organization of the Bacterial Cysteine Synthase Complex, a Potential Target for Enhancers of Antibiotic Action

by Brenda Rosa, Marialaura Marchetti, Gianluca Paredi, Heinz Amenitsch, Nina Franko, Roberto Benoni, Barbara Giabbai, Maria Giovanna De Marino, Andrea Mozzarelli, Luca Ronda, Paola Storici, Barbara Campanini and Stefano Bettati

Int. J. Mol. Sci. 2019, 20(20), 5219; https://doi.org/10.3390/ijms20205219 - 21 Oct 2019

Cited by 11 | Viewed by 4595

Abstract

The formation of multienzymatic complexes allows for the fine tuning of many aspects of enzymatic functions, such as efficiency, localization, stability, and moonlighting. Here, we investigated, in solution, the structure of bacterial cysteine synthase (CS) complex. CS is formed by serine acetyltransferase (CysE) and O-acetylserine sulfhydrylase isozyme A (CysK), the enzymes that catalyze the last two steps of cysteine biosynthesis in bacteria. CysK and CysE have been proposed as potential targets for antibiotics, since cysteine and related metabolites are intimately linked to protection of bacterial cells against redox damage and to antibiotic resistance. We applied a combined approach of small-angle X-ray scattering (SAXS) spectroscopy and protein painting to obtain a model for the solution structure of CS. Protein painting allowed the identification of protein–protein interaction hotspots that were then used as constrains to model the CS quaternary assembly inside the SAXS envelope. We demonstrate that the active site entrance of CysK is involved in complex formation, as suggested by site-directed mutagenesis and functional studies. Furthermore, complex formation involves a conformational change in one CysK subunit that is likely transmitted through the dimer interface to the other subunit, with a regulatory effect. Finally, SAXS data indicate that only one active site of CysK is involved in direct interaction with CysE and unambiguously unveil the quaternary arrangement of CS. Full article

(This article belongs to the Special Issue Non-Essential Targets in the Development of Antibiotics and Enhancers of Antimicrobial Therapy)

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13 pages, 2312 KiB

Open AccessArticle

Identification and Characterization of Approved Drugs and Drug-Like Compounds as Covalent Escherichia coli ClpP Inhibitors

by Elisa Sassetti, Cristina Durante Cruz, Päivi Tammela, Mathias Winterhalter, Koen Augustyns, Philip Gribbon and Björn Windshügel

Int. J. Mol. Sci. 2019, 20(11), 2686; https://doi.org/10.3390/ijms20112686 - 31 May 2019

Cited by 6 | Viewed by 4463

Abstract

The serine protease Caseinolytic protease subunit P (ClpP) plays an important role for protein homeostasis in bacteria and contributes to various developmental processes, as well as virulence. Therefore, ClpP is considered as a potential drug target in Gram-positive and Gram-negative bacteria. In this study, we utilized a biochemical assay to screen several small molecule libraries of approved and investigational drugs for Escherichia coli ClpP inhibitors. The approved drugs bortezomib, cefmetazole, cisplatin, as well as the investigational drug cDPCP, and the protease inhibitor 3,4-dichloroisocoumarin (3,4-DIC) emerged as ClpP inhibitors with IC₅₀ values ranging between 0.04 and 31 µM. Compound profiling of the inhibitors revealed cefmetazole and cisplatin not to inhibit the serine protease bovine α-chymotrypsin, and for cefmetazole no cytotoxicity against three human cell lines was detected. Surface plasmon resonance studies demonstrated all novel ClpP inhibitors to bind covalently to ClpP. Investigation of the potential binding mode for cefmetazole using molecular docking suggested a dual covalent binding to Ser97 and Thr168. While only the antibiotic cefmetazole demonstrated an intrinsic antibacterial effect, cDPCP clearly delayed the bacterial growth recovery time upon chemically induced nitric oxide stress in a ClpP-dependent manner. Full article

(This article belongs to the Special Issue Non-Essential Targets in the Development of Antibiotics and Enhancers of Antimicrobial Therapy)

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Review

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44 pages, 4799 KiB

Open AccessReview

Iron Metabolism at the Interface between Host and Pathogen: From Nutritional Immunity to Antibacterial Development

by Marialaura Marchetti, Omar De Bei, Stefano Bettati, Barbara Campanini, Sandra Kovachka, Eleonora Gianquinto, Francesca Spyrakis and Luca Ronda

Int. J. Mol. Sci. 2020, 21(6), 2145; https://doi.org/10.3390/ijms21062145 - 20 Mar 2020

Cited by 51 | Viewed by 8759

Abstract

Nutritional immunity is a form of innate immunity widespread in both vertebrates and invertebrates. The term refers to a rich repertoire of mechanisms set up by the host to inhibit bacterial proliferation by sequestering trace minerals (mainly iron, but also zinc and manganese). This strategy, selected by evolution, represents an effective front-line defense against pathogens and has thus inspired the exploitation of iron restriction in the development of innovative antimicrobials or enhancers of antimicrobial therapy. This review focuses on the mechanisms of nutritional immunity, the strategies adopted by opportunistic human pathogen Staphylococcus aureus to circumvent it, and the impact of deletion mutants on the fitness, infectivity, and persistence inside the host. This information finally converges in an overview of the current development of inhibitors targeting the different stages of iron uptake, an as-yet unexploited target in the field of antistaphylococcal drug discovery. Full article

(This article belongs to the Special Issue Non-Essential Targets in the Development of Antibiotics and Enhancers of Antimicrobial Therapy)

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25 pages, 3328 KiB

Open AccessReview

Strategies to Overcome Antimicrobial Resistance (AMR) Making Use of Non-Essential Target Inhibitors: A Review

by Giannamaria Annunziato

Int. J. Mol. Sci. 2019, 20(23), 5844; https://doi.org/10.3390/ijms20235844 - 21 Nov 2019

Cited by 149 | Viewed by 13504

Abstract

Antibiotics have always been considered as one of the most relevant discoveries of the twentieth century. Unfortunately, the dawn of the antibiotic era has sadly corresponded to the rise of the phenomenon of antimicrobial resistance (AMR), which is a natural process whereby microbes evolve in such a way to withstand the action of drugs. In this context, the identification of new potential antimicrobial targets and/or the identification of new chemical entities as antimicrobial drugs are in great demand. To date, among the many possible approaches used to deal with antibiotic resistance is the use of antibiotic adjuvants that hit bacterial non-essential targets. In this review, the author focuses on the discovery of antibiotic adjuvants and on new tools to study and reduce the prevalence of resistant bacterial infections. Full article

(This article belongs to the Special Issue Non-Essential Targets in the Development of Antibiotics and Enhancers of Antimicrobial Therapy)

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30 pages, 2227 KiB

Open AccessReview

An Overview of Drug Resistance in Protozoal Diseases

by Rita Capela, Rui Moreira and Francisca Lopes

Int. J. Mol. Sci. 2019, 20(22), 5748; https://doi.org/10.3390/ijms20225748 - 15 Nov 2019

Cited by 123 | Viewed by 10848

Abstract

Protozoan diseases continue to be a worldwide social and economic health problem. Increased drug resistance, emerging cross resistance, and lack of new drugs with novel mechanisms of action significantly reduce the effectiveness of current antiprotozoal therapies. While drug resistance associated to anti-infective agents is a reality, society seems to remain unaware of its proportions and consequences. Parasites usually develops ingenious and innovative mechanisms to achieve drug resistance, which requires more research and investment to fight it. In this review, drug resistance developed by protozoan parasites Plasmodium, Leishmania, and Trypanosoma will be discussed. Full article

(This article belongs to the Special Issue Non-Essential Targets in the Development of Antibiotics and Enhancers of Antimicrobial Therapy)

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23 pages, 619 KiB

Open AccessReview

Opportunities for Overcoming Mycobacterium tuberculosis Drug Resistance: Emerging Mycobacterial Targets and Host-Directed Therapy

by Eveline Torfs, Tatiana Piller, Paul Cos and Davie Cappoen

Int. J. Mol. Sci. 2019, 20(12), 2868; https://doi.org/10.3390/ijms20122868 - 12 Jun 2019

Cited by 49 | Viewed by 7503

Abstract

The ever-increasing incidence of drug-resistant Mycobacterium tuberculosis infections has invigorated the focus on the discovery and development of novel treatment options. The discovery and investigation of essential mycobacterial targets is of utmost importance. In addition to the discovery of novel targets, focusing on non-lethal pathways and the use of host-directed therapies has gained interest. These adjunctive treatment options could not only lead to increased antibiotic susceptibility of Mycobacterium tuberculosis, but also have the potential to avoid the emergence of drug resistance. Host-directed therapies, on the other hand, can also reduce the associated lung pathology and improve disease outcome. This review will provide an outline of recent opportunities. Full article

(This article belongs to the Special Issue Non-Essential Targets in the Development of Antibiotics and Enhancers of Antimicrobial Therapy)

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15 pages, 1576 KiB

Open AccessReview

Mechanistic Insights into the Antimicrobial Actions of Metallic Nanoparticles and Their Implications for Multidrug Resistance

by Sibhghatulla Shaikh, Nazia Nazam, Syed Mohd Danish Rizvi, Khurshid Ahmad, Mohammad Hassan Baig, Eun Ju Lee and Inho Choi

Int. J. Mol. Sci. 2019, 20(10), 2468; https://doi.org/10.3390/ijms20102468 - 18 May 2019

Cited by 353 | Viewed by 11637

Abstract

Multiple drug-resistant bacteria are a severe and growing public health concern. Because relatively few antibiotics have been approved over recent years and because of the inability of existing antibiotics to combat bacterial infections fully, demand for unconventional biocides is intense. Metallic nanoparticles (NPs) offer a novel potential means of fighting bacteria. Although metallic NPs exert their effects through membrane protein damage, superoxide radicals and the generation of ions that interfere with the cell granules leading to the formation of condensed particles, their antimicrobial potential, and mechanisms of action are still debated. This article discusses the action of metallic NPs as antibacterial agents, their mechanism of action, and their effect on bacterial drug resistance. Based on encouraging data about the antibacterial effects of NP/antibiotic combinations, we propose that this concept be thoroughly researched to identify means of combating drug-resistant bacteria. Full article

(This article belongs to the Special Issue Non-Essential Targets in the Development of Antibiotics and Enhancers of Antimicrobial Therapy)

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19 pages, 3174 KiB

Open AccessReview

ClpP Protease, a Promising Antimicrobial Target

by Carlos Moreno-Cinos, Kenneth Goossens, Irene G. Salado, Pieter Van Der Veken, Hans De Winter and Koen Augustyns

Int. J. Mol. Sci. 2019, 20(9), 2232; https://doi.org/10.3390/ijms20092232 - 7 May 2019

Cited by 77 | Viewed by 8525

Abstract

The caseinolytic protease proteolytic subunit (ClpP) is a serine protease playing an important role in proteostasis of eukaryotic organelles and prokaryotic cells. Alteration of ClpP function has been proved to affect the virulence and infectivity of a number of pathogens. Increased bacterial resistance to antibiotics has become a global problem and new classes of antibiotics with novel mechanisms of action are needed. In this regard, ClpP has emerged as an attractive and potentially viable option to tackle pathogen fitness without suffering cross-resistance to established antibiotic classes and, when not an essential target, without causing an evolutionary selection pressure. This opens a greater window of opportunity for the host immune system to clear the infection by itself or by co-administration with commonly prescribed antibiotics. A comprehensive overview of the function, regulation and structure of ClpP across the different organisms is given. Discussion about mechanism of action of this protease in bacterial pathogenesis and human diseases are outlined, focusing on the compounds developed in order to target the activation or inhibition of ClpP. Full article

(This article belongs to the Special Issue Non-Essential Targets in the Development of Antibiotics and Enhancers of Antimicrobial Therapy)

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