Antibiotic Hybrids: the Next Generation of Agents and Adjuvants against Gram-Negative Pathogens?

SUMMARYThe global incidence of drug-resistant Gram-negative bacillary infections has been increasing, and there is a dire need to develop novel strategies to overcome this problem. Intrinsic resistance in Gram-negative bacteria, such as their protective outer membrane and constitutively overexpressed efflux pumps, is a major survival weapon that renders them refractory to current antibiotics. Several potential avenues to overcome this problem have been at the heart of antibiotic drug discovery in the past few decades. We review some of these strategies, with emphasis on antibiotic hybrids either as stand-alone antibacterial agents or as adjuvants that potentiate a primary antibiotic in Gram-negative bacteria. Antibiotic hybrid is defined in this review as a synthetic construct of two or more pharmacophores belonging to an established agent known to elicit a desired antimicrobial effect. The concepts, advances, and challenges of antibiotic hybrids are elaborated in this article. Moreover, we discuss several antibiotic hybrids that were or are in clinical evaluation. Mechanistic insights into how tobramycin-based antibiotic hybrids are able to potentiate legacy antibiotics in multidrug-resistant Gram-negative bacilli are also highlighted. Antibiotic hybrids indeed have a promising future as a therapeutic strategy to overcome drug resistance in Gram-negative pathogens and/or expand the usefulness of our current antibiotic arsenal.

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Benzydamine Reverses TMexCD-TOprJ-Mediated High-Level Tigecycline Resistance in Gram-Negative Bacteria

Pharmaceuticals ◽

10.3390/ph14090907 ◽

2021 ◽

Vol 14 (9) ◽

pp. 907

Author(s):

Ziwen Tong ◽

Tianqi Xu ◽

Tian Deng ◽

Jingru Shi ◽

Zhiqiang Wang ◽

...

Keyword(s):

Therapeutic Strategy ◽

Galleria Mellonella ◽

Efflux Pump ◽

Multidrug Resistant ◽

Gram Negative Bacteria ◽

Drug Resistant ◽

Intracellular Accumulation ◽

Gram Negative ◽

Resistance Nodulation Division ◽

High Level

Recently, a novel efflux pump gene cluster called tmexCD1-toprJ1 and its variants have been identified, which undermine the antibacterial activity of tigecycline, one of the last remaining options effective against multidrug-resistant (MDR) Gram-negative bacteria. Herein, we report the potent synergistic effect of the non-steroidal anti-inflammatory drug benzydamine in combination with tigecycline at sub-inhibitory concentrations against various temxCD-toprJ-positive Gram-negative pathogens. The combination of benzydamine and tigecycline killed all drug-resistant pathogens during 24 h of incubation. In addition, the evolution of tigecycline resistance was significantly suppressed in the presence of benzydamine. Studies on the mechanisms of synergism showed that benzydamine disrupted the bacterial proton motive force and the functionality of this kind of novel plasmid-encoded resistance-nodulation-division efflux pump, thereby promoting the intracellular accumulation of tigecycline. Most importantly, the combination therapy of benzydamine and tigecycline effectively improved the survival of Galleria mellonella larvae compared to tigecycline monotherapy. Our findings provide a promising drug combination therapeutic strategy for combating superbugs carrying the tmexCD-toprJ gene.

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Curative Treatment of Severe Gram-Negative Bacterial Infections by a New Class of Antibiotics Targeting LpxC

mBio ◽

10.1128/mbio.00674-17 ◽

2017 ◽

Vol 8 (4) ◽

Cited By ~ 13

Author(s):

Nadine Lemaître ◽

Xiaofei Liang ◽

Javaria Najeeb ◽

Chul-Jin Lee ◽

Marie Titecat ◽

...

Keyword(s):

Bacterial Infections ◽

Biosynthetic Pathway ◽

Lipid A ◽

Multidrug Resistant ◽

Gram Negative Bacteria ◽

Drug Resistant ◽

Bubonic Plague ◽

Gram Negative ◽

New Class

ABSTRACT The infectious diseases caused by multidrug-resistant bacteria pose serious threats to humankind. It has been suggested that an antibiotic targeting LpxC of the lipid A biosynthetic pathway in Gram-negative bacteria is a promising strategy for curing Gram-negative bacterial infections. However, experimental proof of this concept is lacking. Here, we describe our discovery and characterization of a biphenylacetylene-based inhibitor of LpxC, an essential enzyme in the biosynthesis of the lipid A component of the outer membrane of Gram-negative bacteria. The compound LPC-069 has no known adverse effects in mice and is effective in vitro against a broad panel of Gram-negative clinical isolates, including several multiresistant and extremely drug-resistant strains involved in nosocomial infections. Furthermore, LPC-069 is curative in a murine model of one of the most severe human diseases, bubonic plague, which is caused by the Gram-negative bacterium Yersinia pestis. Our results demonstrate the safety and efficacy of LpxC inhibitors as a new class of antibiotic against fatal infections caused by extremely virulent pathogens. The present findings also highlight the potential of LpxC inhibitors for clinical development as therapeutics for infections caused by multidrug-resistant bacteria. IMPORTANCE The rapid spread of antimicrobial resistance among Gram-negative bacilli highlights the urgent need for new antibiotics. Here, we describe a new class of antibiotics lacking cross-resistance with conventional antibiotics. The compounds inhibit LpxC, a key enzyme in the lipid A biosynthetic pathway in Gram-negative bacteria, and are active in vitro against a broad panel of clinical isolates of Gram-negative bacilli involved in nosocomial and community infections. The present study also constitutes the first demonstration of the curative treatment of bubonic plague by a novel, broad-spectrum antibiotic targeting LpxC. Hence, the data highlight the therapeutic potential of LpxC inhibitors against a wide variety of Gram-negative bacterial infections, including the most severe ones caused by Y. pestis and by multidrug-resistant and extensively drug-resistant carbapenemase-producing strains. IMPORTANCE The rapid spread of antimicrobial resistance among Gram-negative bacilli highlights the urgent need for new antibiotics. Here, we describe a new class of antibiotics lacking cross-resistance with conventional antibiotics. The compounds inhibit LpxC, a key enzyme in the lipid A biosynthetic pathway in Gram-negative bacteria, and are active in vitro against a broad panel of clinical isolates of Gram-negative bacilli involved in nosocomial and community infections. The present study also constitutes the first demonstration of the curative treatment of bubonic plague by a novel, broad-spectrum antibiotic targeting LpxC. Hence, the data highlight the therapeutic potential of LpxC inhibitors against a wide variety of Gram-negative bacterial infections, including the most severe ones caused by Y. pestis and by multidrug-resistant and extensively drug-resistant carbapenemase-producing strains.

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Phenotypic characterization of carbapenem non-susceptible gram-negative bacilli isolated from clinical specimens

PLoS ONE ◽

10.1371/journal.pone.0256556 ◽

2021 ◽

Vol 16 (12) ◽

pp. e0256556

Author(s):

Abera Abdeta ◽

Adane Bitew ◽

Surafel Fentaw ◽

Estifanos Tsige ◽

Dawit Assefa ◽

...

Keyword(s):

Public Health ◽

Prevention And Control ◽

Multidrug Resistant ◽

Gram Negative Bacteria ◽

Drug Resistant ◽

Gram Negative ◽

Extensively Drug Resistant ◽

Gram Negative Organisms ◽

And Control ◽

Public Health Institute

Background Multidrug resistant, extremely drug-resistant, pan-drug resistant, carbapenem-resistant, and carbapenemase-producing gram-negative bacteria are becoming more common in health care settings and are posing a growing threat to public health. Objective The study was aimed to detect and phenotypically characterize carbapenem no- susceptible gram-negative bacilli at the Ethiopian Public Health Institute. Materials and methods A prospective cross-sectional study was conducted from June 30, 2019, to May 30, 2020, at the national reference laboratory of the Ethiopian Public Health Institute. Clinical samples were collected, inoculated, and incubated for each sample in accordance with standard protocol. Antimicrobial susceptibility testing was conducted using Kirby-Bauer disk diffusion method. Identification was done using the traditional biochemical method. Multidrug-resistant and extensively drug-resistant isolates were classified using a standardized definition established by the European Centre for Disease Prevention and Control and the United States Centers for Disease Prevention and Control. Gram-negative organisms with reduced susceptibility to carbapenem antibiotics were considered candidate carbapenemase producers and subjected to modified carbapenem inactivation and simplified carbapenem inactivation methods. Meropenem with EDTA was used to differentiate metallo-β-lactamase (MBL) from serine carbapenemase. Meropenem (MRP)/meropenem + phenylboronic acid (MBO) were used to differentiate Klebsiella pneumoniae carbapenemase (KPC) from other serine carbapenemase producing gram-negative organisms. Results A total of 1,337 clinical specimens were analyzed, of which 429 gram-negative bacterial isolates were recovered. Out of 429 isolates, 319, 74, and 36 were Enterobacterales, Acinetobacter species, and Pseudomonas aeruginosa respectively. In our study, the prevalence of multidrug-resistant, extensively drug-resistant, carbapenemase-producing, and carbapenem nonsusceptible gram-negative bacilli were 45.2%, 7.7%, 5.4%, and 15.4% respectively. Out of 429 isolates, 66 demonstrated reduced susceptibility to the antibiotics meropenem and imipenem. These isolates were tested for carbapenemase production of which 34.8% (23/66) were carbapenemase producers. Out of 23 carbapenemase positive gram-negative bacteria, ten (10) and thirteen (13) were metallo-beta-lactamase and serine carbapenemase respectively. Three of 13 serine carbapenemase positive organisms were Klebsiella pneumoniae carbapenemase. Conclusion This study revealed an alarming level of antimicrobial resistance (AMR), with a high prevalence of multidrug-resistant (MDR) and extremely drug-resistant, carbapenemase-producing gram-negative bacteria, particularly among intensive care unit patients at the health facility level. These findings point to a scenario in which clinical management of infected patients becomes increasingly difficult and necessitates the use of “last-resort” antimicrobials likely exacerbating the magnitude of the global AMR crisis. This mandates robust AMR monitoring and an infection prevention and control program.

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An Overview of the Activities of Cefiderocol Against Sensitive and Multidrug- Resistant (MDR) Bacteria

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520666200818211405 ◽

2020 ◽

Vol 20 (18) ◽

pp. 1908-1916

Author(s):

Manaf AlMatar ◽

Osman Albarri ◽

Essam A. Makky ◽

Işıl Var ◽

Fatih Köksal

Keyword(s):

Multidrug Resistant ◽

Therapeutic Agents ◽

Health Concern ◽

Side Chain ◽

Gram Negative Bacteria ◽

Drug Resistant ◽

Public Health Concern ◽

Gram Negative ◽

Penicillin Binding Proteins ◽

The Public

The need for new therapeutics and drug delivery systems has become necessary owing to the public health concern associated with the emergence of multidrug-resistant microorganisms. Among the newly discovered therapeutic agents is cefiderocol, which was discovered by Shionogi Company, Japan as an injectable siderophore cephalosporin. Just like the other β-lactam antibiotics, cefiderocol exhibits antibacterial activity via cell wall synthesis inhibition, especially in Gram negative bacteria (GNB); it binds to the penicillin-binding proteins, but its unique attribute is that it crosses the periplasmic space of bacteria owing to its siderophore-like attribute; it also resists the activity of β-lactamases. Among all the synthesized compounds with the modified C-7 side chain, cefiderocol (3) presented the best and well-balanced activity against multi-drug resistant (MDR) Gram negative bacteria, including those that are resistant to carbapenem. İn this article, an overview of the recent studies on cefiderocol was presented.

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Resistance of uropathogens to antibacterial agents: Emerging threats, trends and treatments

Archivio Italiano di Urologia e Andrologia ◽

10.4081/aiua.2018.2.85 ◽

2018 ◽

Vol 90 (2) ◽

pp. 85 ◽

Cited By ~ 3

Author(s):

Gianpaolo Perletti ◽

Vittorio Magri ◽

Tommaso Cai ◽

Konstantinos Stamatiou ◽

Alberto Trinchieri ◽

...

Keyword(s):

Antibacterial Agents ◽

Multidrug Resistant ◽

Medical Emergency ◽

Fluoroquinolone Resistance ◽

Drug Resistant ◽

Gram Negative ◽

Resistance Determinants ◽

Rapid Spread ◽

The World ◽

Tract Infections

Urinary tract infections are among the most common infectious diseases in humans. Today, resistance to nearly all antimicrobial classes is dramatically growing, and extremely drug-resistant or even pan-drug resistant pathogens are increasingly isolated around the world. It is foreseen that in the next decades the world will be facing a major medical emergency generated by the rapid spread of pathogens carrying resistance determinants of unprecedented power. Carbapenemase-producing Enterobacteriaceae, multidrug- resistant Enterococci and fluoroquinolone resistance determinants in both Gram-negative and Gram-positive uropathogens are among the greatest emergencies. In this article, the major emerging threats of particular interest to urologists are reviewed, worldwide resistance trends are illustrated, and novel and older – but still active – recommended drugs are summarized.

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Drugs for Gram-Negative Bugs From 2010–2019: A Decade in Review

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa276 ◽

2020 ◽

Vol 7 (7) ◽

Author(s):

Benjamin A Pontefract ◽

Hong T Ho ◽

Alexandria Crain ◽

Madan K Kharel ◽

S Eric Nybo

Keyword(s):

Bacterial Infections ◽

Antibacterial Agents ◽

Web Of Science ◽

Scholarly Activity ◽

Gram Negative Bacteria ◽

Medical Subject Headings ◽

Gram Negative ◽

Isi Web Of Science ◽

The Past ◽

Made In

Abstract A literature review spanning January 1, 2010, to December 31, 2019, was conducted using the PubMed and ISI Web of Science databases to determine the breadth of publication activity in the area of gram-negative bacteria antimicrobial therapy. The number of articles was used as a reflection of scholarly activity. First, PubMed was searched using the following Medical Subject Headings (MeSH): antibacterial agents, Enterobacteriaceae, Acinetobacter, and Pseudomonas. A total of 12 643 articles were identified within PubMed, and 77 862 articles were identified within ISI Web of Science that included these terms. Second, these articles were categorized by antibiotic class to identify relative contributions to the literature by drug category. Third, these studies were used to identify key trends in the treatment of gram-negative bacterial infections from the past decade. This review highlights advances made in the past 10 years in antibacterial pharmacotherapy and some of the challenges that await the next decade of practice.

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Antibiotic–non-antibiotic combinations for combating extremely drug-resistant Gram-negative ‘superbugs’

Essays in Biochemistry ◽

10.1042/ebc20160058 ◽

2017 ◽

Vol 61 (1) ◽

pp. 115-125 ◽

Cited By ~ 35

Author(s):

Elena K. Schneider ◽

Felisa Reyes-Ortega ◽

Tony Velkov ◽

Jian Li

Keyword(s):

Therapeutic Strategy ◽

Polymyxin B ◽

Drug Resistant ◽

Combination Strategy ◽

Gram Negative ◽

Antibiotic Drugs ◽

Antibiotic Drug ◽

The Status ◽

Potential Benefits ◽

Synergistic Combinations

The emergence of antimicrobial resistance of Gram-negative pathogens has become a worldwide crisis. The status quo for combating resistance is to employ synergistic combinations of antibiotics. Faced with this fast-approaching post-antibiotic era, it is critical that we devise strategies to prolong and maximize the clinical efficacy of existing antibiotics. Unfortunately, reports of extremely drug-resistant (XDR) Gram-negative pathogens have become more common. Combining antibiotics such as polymyxin B or the broad-spectrum tetracycline and minocycline with various FDA-approved non-antibiotic drugs have emerged as a novel combination strategy against otherwise untreatable XDR pathogens. This review surveys the available literature on the potential benefits of employing antibiotic–non-antibiotic drug combination therapy. The apex of this review highlights the clinical utility of this novel therapeutic strategy for combating infections caused by ‘superbugs’.

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Mechanistic Study of Synergistic Antimicrobial Effects between Poly (3-hydroxybutyrate) Oligomer and Polyethylene Glycol

10.20944/preprints202010.0231.v1 ◽

2020 ◽

Author(s):

Ziheng Zhang ◽

Jun Li ◽

Linlin Ma ◽

Xingxing Yang ◽

Bin Fei ◽

...

Keyword(s):

Polyethylene Glycol ◽

Antimicrobial Agents ◽

Antimicrobial Effect ◽

Mechanistic Study ◽

Resistant Bacteria ◽

Gram Negative Bacteria ◽

Drug Resistant ◽

Gram Negative ◽

Gram Positive Bacteria ◽

Drug Resistant Bacteria

We reported previously that poly (3-hydroxybutyrate) (PHB) oligomer is an effective antimicrobial agent against gram-positive bacteria, gram-negative bacteria, fungi and multi-drug resistant bacteria. In this work, it was further found that polyethylene glycol (PEG) can promote the antimicrobial effect of PHB oligomer synergistically. Three hypothetic mechanisms were proposed, that is, generation of new antimicrobial components, degradation of PHB macromolecules and dissolution/dispersion of PHB oligomer by PEG. With a series of systematic experiments and characterizations of HPLC-MS, it was deducted that dissolution/dispersion of PHB oligomer dominated the synergistic antimicrobial effect between PHB oligomer and PEG. This work demonstrates a way for promoting antimicrobial effect of PHB oligomer and other antimicrobial agents through improving hydrophilicity.

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Multidrug resistant, extensively drug resistant and pan drug resistant gram negative bacteria at a tertiary care centre in Bhubaneswar

International Journal of Community Medicine and Public Health ◽

10.18203/2394-6040.ijcmph20190170 ◽

2019 ◽

Vol 6 (2) ◽

pp. 567 ◽

Cited By ~ 4

Author(s):

Dipti Pattnaik ◽

Subhra Snigdha Panda ◽

Nipa Singh ◽

Smrutilata Sahoo ◽

Ipsa Mohapatra ◽

...

Keyword(s):

Tertiary Care ◽

Multidrug Resistant ◽

Diffusion Method ◽

Gram Negative Bacteria ◽

Drug Resistant ◽

Gram Negative ◽

Extensively Drug Resistant ◽

Resistant Strains ◽

Drug Resistant Strains ◽

Esbl Producers

Background: Multidrug resistance has emerged as a challenge in health care settings. Again increasing prevalence of multidrug resistant (MDR), extensively drug resistant (XDR) and pan drug resistant (PDR) gram negative bacteria is making the condition more critical because of limited options of antibiotics, increasing morbidity, mortality and hospital stay of the patients. The present study is carried out with an aim to estimate the prevalence of MDR, XDR, PDR gram negative bacteria in a tertiary care hospital.Methods: Total of 912 gram negative bacterial isolates obtained from various samples of indoor patients in a tertiary care hospital, were studied over a period of six months. The bacteria were identified by conventional methods. Antibiotic sensitivity testing was done by Kirby Bauer disc diffusion method. Minimum inhibitory concentration (MIC) of antibiotics for the resistant isolates were detected by Vitek-2 automated method. MDR, XDR and PDR were determined according to the definitions suggested by European Centre for Disease Prevention and Control (ECDC), and Centers for Disease Control and Prevention (CDC). Prevalence of extended spectrum beta lactamase (ESBL) producers was estimated.Results: Out of 912 isolates, prevalence of MDR, XDR and PDR were 66.12%, 34.32% and 0.98% respectively. Prevalence of MDR and XDR were higher in ICUs than clinical wards (p<0.0001). Prevalence of ESBL producers was 48.4%.Conclusions: The study highlights increased prevalence of multidrug resistant and extensively drug resistant strains in our hospital. Stringent surveillance, proper implementation of hospital infection control practices and antimicrobial stewardship will help in limiting the emergence and spread of drug resistant strains.

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Detection and phenotypic characterization of carbapenem non susceptible gram-negative bacilli isolated from clinical specimens

10.1101/2021.08.17.456671 ◽

2021 ◽

Author(s):

Abera Abdeta ◽

Adane Bitew ◽

Surafel Fentaw ◽

Estifanos Tsige ◽

Dawit Assefa ◽

...

Keyword(s):

Public Health ◽

Prevention And Control ◽

Multidrug Resistant ◽

Gram Negative Bacteria ◽

Drug Resistant ◽

Gram Negative ◽

Clinical Specimens ◽

Extensively Drug Resistant ◽

And Control ◽

Public Health Institute

Background Multi-drug resistant, extremely drug-resistant, pan-drug resistant, carbapenem-resistant, and carbapenemase-producing gram-negative bacteria are becoming more common in health care settings and are posing a growing threat to public health. Objective The study was aimed to determine the magnitude of multi-drug resistant, extremely drug-resistant, carbapenem non-susceptible, and carbapenemase-producing gram-negative bacilli at Ethiopian Public Health Institute. Materials and methods Prospective cross-sectional study was conducted from June 30, 2019, to May 30, 2020, at the national reference laboratory of the Ethiopian Public Health Institute. Clinical samples were collected, inoculated, and incubated in accordance to standard protocol for each sample. Antimicrobial susceptibility testing was done using Kirby Bauer disk diffusion. Identification was done using the traditional biochemical method. Multidrug-resistant and extensively drug-resistant were classified using a standardized definition established by European Centers for Disease prevention and control and the United States Centers for Disease prevention and control experts. Carbapenemase production was confirmed by modified carbapenem inactivation and a simplified carbapenem inactivation method. Meropenem with EDTA was used to differentiate serine carbapenemase and Metallo β-lactamase. Results A total of 1337 clinical specimens were analyzed, of which 429-gram negative bacilli isolates were recovered. Out of 429 isolates 319, 74, and 36 were Enterobacterales, Acinetobacter species, and P. aeruginosa respectively. In our study, the prevalence of Multidrug-resistant, extensively drug-resistant, Carbapenemase-producing, and carbapenem non-susceptible Gram-negative bacilli were, 45.2%, 7.7%, 5.4%, and 15.4% respectively. Out of 66 isolates screened for Carbapenemase, 34.8% (23/66) were Carbapenemase enzyme producers. Ten out of twenty-three Carbapenemase-positive organisms were Metallo-beta-lactamase producers. Thirteen out of twenty-three isolates were serine carbapenemase producers. Three out of 13 serine Carbapenemase positive organisms were Klebsiella pneumoniae Carbapenemase. Conclusion The finding from this study revealed a high prevalence of Multidrug-resistant, extremely drug-resistant, carbapenemase-producing gram-negative bacteria, particularly among Intensive care unit patients at the health facility level, this necessitates a robust laboratory-based antimicrobial resistance monitoring and infection prevention and control program.

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