The Engineered Antibiotic Peptide PLG0206 Eliminates Biofilms and Is a Potential Treatment for Periprosthetic Joint Infections

Antimicrobial peptides (AMPs) have recently gained attention for their potential to treat diseases related to bacterial and viral infections, as many traditional antimicrobial drugs have reduced efficacy in treating these infections due to the increased prevalence of drug-resistant pathogens. PLG0206, an engineered cationic antibiotic peptide that is 24 residues long, has been designed to address some limitations of other natural AMPs, such as toxicity and limited activity due to pH and ion concentrations. Nonclinical studies have shown that PLG0206 is highly selective for targeting bacterial cells and is not toxic to human blood cells. Antibiofilm experiments demonstrated that PLG0206 is effective at reducing both biotic and abiotic biofilm burdens following direct biofilm contact. PLG0206 has rapid and broad-spectrum activity against both Gram-positive and Gram-negative bacteria that are implicated as etiologic agents in periprosthetic joint infections, including multidrug-resistant ESKAPE pathogens and colistin-resistant isolates. A recent first-in-human study demonstrated that PLG0206 is well tolerated and safe as an intravenous infusion in healthy volunteers. Studies are planned to determine the efficacy of PLG0206 in patients for the treatment of periprosthetic joint infections. This review summarizes the chemistry, pharmacology, and microbiology of PLG0206 and explores its current preclinical, clinical, and regulatory status.

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Liposomes as Antibiotic Delivery Systems: A Promising Nanotechnological Strategy against Antimicrobial Resistance

Molecules ◽

10.3390/molecules26072047 ◽

2021 ◽

Vol 26 (7) ◽

pp. 2047

Author(s):

Magda Ferreira ◽

Maria Ogren ◽

Joana N. R. Dias ◽

Marta Silva ◽

Solange Gil ◽

...

Keyword(s):

Antimicrobial Resistance ◽

Bacterial Infections ◽

Private Investment ◽

Therapeutic Index ◽

Multidrug Resistant ◽

Current Treatment ◽

Delivery Systems ◽

Resistant Bacteria ◽

Bacterial Cells ◽

Antimicrobial Drugs

Antimicrobial drugs are key tools to prevent and treat bacterial infections. Despite the early success of antibiotics, the current treatment of bacterial infections faces serious challenges due to the emergence and spread of resistant bacteria. Moreover, the decline of research and private investment in new antibiotics further aggravates this antibiotic crisis era. Overcoming the complexity of antimicrobial resistance must go beyond the search of new classes of antibiotics and include the development of alternative solutions. The evolution of nanomedicine has allowed the design of new drug delivery systems with improved therapeutic index for the incorporated compounds. One of the most promising strategies is their association to lipid-based delivery (nano)systems. A drug’s encapsulation in liposomes has been demonstrated to increase its accumulation at the infection site, minimizing drug toxicity and protecting the antibiotic from peripheral degradation. In addition, liposomes may be designed to fuse with bacterial cells, holding the potential to overcome antimicrobial resistance and biofilm formation and constituting a promising solution for the treatment of potential fatal multidrug-resistant bacterial infections, such as methicillin resistant Staphylococcus aureus. In this review, we aim to address the applicability of antibiotic encapsulated liposomes as an effective therapeutic strategy for bacterial infections.

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Broad-spectrum activity of a novel antibiotic peptide against multidrug-resistant veterinary isolates

The Veterinary Journal ◽

10.1016/j.tvjl.2013.08.020 ◽

2013 ◽

Vol 198 (2) ◽

pp. 534-537 ◽

Cited By ~ 9

Author(s):

Clotilde Silvia Cabassi ◽

Simone Taddei ◽

Sandro Cavirani ◽

Maria Cristina Baroni ◽

Paolo Sansoni ◽

...

Keyword(s):

Broad Spectrum ◽

Multidrug Resistant ◽

Spectrum Activity ◽

Antibiotic Peptide ◽

Broad Spectrum Activity

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ACUTE RESPIRATORY DISEASES

PEDIATRICS ◽

10.1542/peds.19.1.129 ◽

1957 ◽

Vol 19 (1) ◽

pp. 129-141

Author(s):

John M. Adams

Keyword(s):

Bacterial Infections ◽

Respiratory Diseases ◽

Viral Infections ◽

Lymphocytic Choriomeningitis ◽

Large Field ◽

Virus Infections ◽

Antimicrobial Drugs ◽

Therapeutic Drugs ◽

Etiologic Agents ◽

Rickettsial Diseases

This review might well be regarded as a summary of present knowledge of the large field of respiratory diseases and a brief review of the salient features, concerned primarily with the etiologic, pathogenic and therapeutic considerations. The etiologic, rather than the anatomic, approach to diagnosis is emphasized in order that an intelligent attitude towards therapy might be developed. The recent advances in discovery of new etiologic agents, e.g., adenoviruses, is discussed in some detail. Differential diagnosis includes such diseases as vesicular pharyngitis, lymphocytic choriomeningitis virus infections, infections mononucleosis, poliomyelitis, ornithosis, and rickettsial diseases. Specific use of antimicrobial drugs for certain viral infections is emphasized. Dosage of available therapeutic drugs is detailed for the diseases in which they have been shown to be effective, such as rickettsial diseases, ornithosis, and complicating bacterial infections. Prophylactic uses are outlined and a warning against the uncritical use of such therapy is given. Many problems remain unsolved, but rapid progress is being made.

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Prevention and Killing Efficacy of Carbapenem Resistant Enterobacteriaceae (CRE) and Vancomycin Resistant Enterococci (VRE) Biofilms by Antibiotic-Loaded Calcium Sulfate Beads

Materials ◽

10.3390/ma13153258 ◽

2020 ◽

Vol 13 (15) ◽

pp. 3258

Author(s):

Paul Stoodley ◽

Jacob Brooks ◽

Casey W. Peters ◽

Nan Jiang ◽

Craig P. Delury ◽

...

Keyword(s):

Biofilm Formation ◽

Calcium Sulfate ◽

Multidrug Resistant ◽

Bacterial Cells ◽

Joint Infections ◽

Carbapenem Resistant ◽

Vancomycin Resistant Enterococci ◽

Confocal Images ◽

Vancomycin Resistant ◽

Carbapenem Resistant Enterobacteriaceae

Carbapenem-resistant Enterobacteriaceae (CRE) and vancomycin-resistant Enterococci (VRE) have emerged as multidrug-resistant (MDR) pathogens associated with periprosthetic joint infections (PJI). In this study, we evaluated the efficacy of antibiotic-loaded calcium sulfate beads (ALCSB) in inhibiting bacterial growth, encouraging biofilm formation and killing preformed biofilms of CRE and VRE. Three strains of Klebsiella pneumoniae (KP) and a strain of Enterococcus faecalis (EF) were used. ALCSB of 4.8-mm diameter were loaded with vancomycin (V) and gentamicin (G), V and rifampicin (R), V and tobramycin (T) or R and meropenem (M), and placed onto tryptic soy agar (TSA), spread with one of the test strains and incubated for 24 h at 37 °C. Beads were transferred daily onto fresh TSA spread plates and the zone of inhibition (ZOI) was recorded until no inhibition was observed. ALCSB containing R + M or R + V produced the most extensive ZOI up to 5 weeks. Biofilm prevention efficacy was investigated by challenging ALCSB daily with 5 × 105 CFU/mL bacterial cells and analyzing for biofilm formation at challenges 1, 2 and 3. In the biofilm killing experiments, ALCSB were added to pre-grown 3-day biofilms of KP and EF strains, which were then analyzed at days 1 and 3 post-exposure. The CFU counts and confocal images of the attached cells showed that ALCSB treatment reduced colonization and biofilm formation significantly (5–7 logs) with combinations of R + M or R + V, compared to unloaded beads. This study provides evidence that the local release of antibiotics from ALCSB may be useful in treating the biofilms of multidrug-resistant strains of CRE and VRE.

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Antimicrobial Peptides: A Promising Avenue for Human Healthcare

Current Pharmaceutical Biotechnology ◽

10.2174/1389201020666191011121722 ◽

2020 ◽

Vol 21 (2) ◽

pp. 90-96 ◽

Cited By ~ 2

Author(s):

Girish M. Bhopale

Keyword(s):

Antimicrobial Peptides ◽

Antimicrobial Peptide ◽

Antimicrobial Agents ◽

Current Status ◽

Antimicrobial Drugs ◽

Spectrum Activity ◽

Low Levels ◽

Human Healthcare ◽

Broad Spectrum Activity ◽

Promising Avenue

Antimicrobial drugs resistant microbes have been observed worldwide and therefore alternative development of antimicrobial peptides has gained interest in human healthcare. Enormous progress has been made in the development of antimicrobial peptide during the last decade due to major advantages of AMPs such as broad-spectrum activity and low levels of induced resistance over the current antimicrobial agents. This review briefly provides various categories of AMP, their physicochemical properties and mechanism of action which governs their penetration into microbial cell. Further, the recent information on current status of antimicrobial peptide development, their applications and perspective in human healthcare are also described.

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Multidrug Resistence Prevalence in COVID Area

Life ◽

10.3390/life11070601 ◽

2021 ◽

Vol 11 (7) ◽

pp. 601

Author(s):

Caterina Aurilio ◽

Pasquale Sansone ◽

Antonella Paladini ◽

Manlio Barbarisi ◽

Francesco Coppolino ◽

...

Keyword(s):

Bacterial Resistance ◽

Respiratory Infections ◽

Prolonged Mechanical Ventilation ◽

Viral Disease ◽

Multidrug Resistant ◽

Resistant Bacteria ◽

Antimicrobial Drugs ◽

Infected People ◽

Therapeutic Procedures ◽

Viral Respiratory Infections

Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is often complicated by severe acute respiratory syndrome. The new coronavirus outbreak started in China in December 2019 and rapidly spread around the world. The high diffusibility of the virus was the reason for the outbreak of the pandemic viral disease, reaching more than 100 million infected people globally by the first three months of 2021. In the various treatments used up to now, the use of antimicrobial drugs for the management, especially of bacterial co-infections, is very frequent in patients admitted to intensive care. In addition, critically ill patients with SARS-CoV-2 infection are subjected to prolonged mechanical ventilation and other therapeutic procedures often responsible for developing hospital co-infections due to multidrug-resistant bacteria. Co-infections contribute to the increase in the morbidity–mortality of viral respiratory infections. We performed this study to review the recent articles published on the antibiotic bacterial resistance and viruses to predict risk factors of coronavirus disease 2019 and to assess the multidrug resistance in patients hospitalized in the COVID-19 area.

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A molecular architectural design that promises potent antimicrobial activity against multidrug-resistant pathogens

NPG Asia Materials ◽

10.1038/s41427-021-00287-y ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Bing Yuan ◽

Jiaojiao Liu ◽

Zhixiong Deng ◽

Lin Wei ◽

Wenwen Li ◽

...

Keyword(s):

Architectural Design ◽

Building Blocks ◽

Multidrug Resistant ◽

In Vitro Cytotoxicity ◽

Antimicrobial Drugs ◽

Minimal Inhibitory Concentrations ◽

Antimicrobial Efficiency ◽

Multidrug Resistant Pathogens

AbstractAddressing the devastating threat of drug-resistant pathogens requires the discovery of new antibiotics with advanced action mechanisms and/or novel strategies for drug design. Herein, from a biophysical perspective, we design a class of synthetic antibacterial complexes with specialized architectures based on melittin (Mel), a natural antimicrobial peptide, and poly(ethylene glycol) (PEG), a clinically available agent, as building blocks that show potent and architecture-modulated antibacterial activity. Among the complexes, the flexibly linear complex consisting of one Mel terminally connected with a long-chained PEG (e.g., PEG12k–1*Mel) shows the most pronounced improvement in performance compared with pristine Mel, with up to 500% improvement in antimicrobial efficiency, excellent in vitro activity against multidrug-resistant pathogens (over a range of minimal inhibitory concentrations of 2–32 µg mL−1), a 68% decrease in in vitro cytotoxicity, and a 57% decrease in in vivo acute toxicity. A lipid-specific mode of action in membrane recognition and an accelerated “channel” effect in perforating the bacterial membrane of the complex are described. Our results introduce a new way to design highly efficient and low-toxicity antimicrobial drugs based on architectural modulations with clinically available agents.

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Radiation-Inactivated Acinetobacter baumannii Vaccine Candidates

Vaccines ◽

10.3390/vaccines9020096 ◽

2021 ◽

Vol 9 (2) ◽

pp. 96

Author(s):

Stephen J. Dollery ◽

Daniel V. Zurawski ◽

Elena K. Gaidamakova ◽

Vera Y. Matrosova ◽

John K. Tobin ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Treatment Options ◽

Bacterial Pathogen ◽

Multidrug Resistant ◽

Bacterial Cells ◽

Wound Infections ◽

Protein Profiles ◽

Vaccine Candidates ◽

Rich Media ◽

Life Threatening

Acinetobacter baumannii is a bacterial pathogen that is often multidrug-resistant (MDR) and causes a range of life-threatening illnesses, including pneumonia, septicemia, and wound infections. Some antibiotic treatments can reduce mortality if dosed early enough before an infection progresses, but there are few other treatment options when it comes to MDR-infection. Although several prophylactic strategies have been assessed, no vaccine candidates have advanced to clinical trials or have been approved. Herein, we rapidly produced protective whole-cell immunogens from planktonic and biofilm-like cultures of A. baumannii, strain AB5075 grown using a variety of methods. After selecting a panel of five cultures based on distinct protein profiles, replicative activity was extinguished by exposure to 10 kGy gamma radiation in the presence of a Deinococcus antioxidant complex composed of manganous (Mn2+) ions, a decapeptide, and orthophosphate. Mn2+ antioxidants prevent hydroxylation and carbonylation of irradiated proteins, but do not protect nucleic acids, yielding replication-deficient immunogenic A. baumannii vaccine candidates. Mice were immunized and boosted twice with 1.0 × 107 irradiated bacterial cells and then challenged intranasally with AB5075 using two mouse models. Planktonic cultures grown for 16 h in rich media and biofilm cultures grown in static cultures underneath minimal (M9) media stimulated immunity that led to 80–100% protection.

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1293. Sulbactam-durlobactam is active against recent, multi-drug resistant Acinetobacter baumannii clinical isolates from the Middle East

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1476 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S662-S662

Author(s):

Alita Miller ◽

Sarah McLeod ◽

Samir Moussa ◽

Meredith Hackel

Keyword(s):

Antibacterial Activity ◽

Middle East ◽

Acinetobacter Baumannii ◽

United Arab Emirates ◽

Blood Stream ◽

Multidrug Resistant ◽

Clinical Isolates ◽

Surveillance Systems ◽

Spectrum Activity

Abstract Background The incidence of infections caused by multidrug-resistant (MDR) Acinetobacter baumannii (Ab) is increasing at an alarming rate in certain regions of the world, including the Middle East. Sulbactam (SUL) has intrinsic antibacterial activity against Ab; however, the prevalence of β-lactamases in Ab has limited its therapeutic utility. Durlobactam (DUR, formerly ETX2514) is a diazabicyclooctenone β-lactamase inhibitor with broad-spectrum activity against Ambler class A, C and D β-lactamases that restores SUL activity in vitro against MDR Ab. SUL-DUR is an antibiotic designed to treat serious infections caused by Acinetobacter, including multidrug-resistant strains, that is currently in Phase 3 clinical development. In global surveillance studies of >3600 isolates from 2012-2017, the MIC90 of SUL-DUR was 2 mg/L. Although surveillance systems to monitor MDR infections in the Middle East are currently being established, quantitative, prevalence-based data are not yet available. Therefore, the potency of SUL-DUR was determined against 190 recent, diverse Ab clinical isolates from this region. Methods 190 Ab isolates were collected between 2016 - 2018 from medical centers located in Israel (N = 47), Jordan (N = 36), Qatar (N = 13), Kuwait (N = 42), Lebanon (N = 8), Saudi Arabia (N = 24) and United Arab Emirates (N = 20). Seventy-five percent and 20.5% of these isolates were from respiratory and blood stream infections, respectively. Susceptibility to SUL-DUR and comparator agents was performed according to CLSI guidelines, and data analysis was performed using CLSI and EUCAST breakpoint criteria where available. Results This collection of isolates was 86% carbapenem-resistant and 90% sulbactam-resistant (based on a breakpoint of 4 mg/L). The addition of SUL-DUR (fixed at 4 mg/L) decreased the sulbactam MIC90 from 64 mg/L to 4 mg/L. Only 3 isolates (1.6%) had SUL-DUR MIC values of > 4 mg/L. This potency was consistent across countries, sources of infection and subsets of resistance phenotypes. Conclusion SUL-DUR demonstrated potent antibacterial activity against recent clinical isolates of Ab from the Middle East, including MDR isolates. These data support the global development of SUL-DUR for the treatment of MDR Ab infections. Disclosures Alita Miller, PhD, Entasis Therapeutics (Employee) Sarah McLeod, PhD, Entasis Therapeutics (Employee) Samir Moussa, PhD, Entasis Therapeutics (Employee)

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Presence of the neonatal Staphylococcus capitis outbreak clone (NRCS-A) in prosthetic joint infections

Scientific Reports ◽

10.1038/s41598-020-79225-x ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Staffan Tevell ◽

Sharmin Baig ◽

Bengt Hellmark ◽

Patricia Martins Simoes ◽

Thierry Wirth ◽

...

Keyword(s):

Neonatal Intensive Care ◽

Bloodstream Infections ◽

Multidrug Resistant ◽

Coagulase Negative Staphylococcus ◽

Nasal Carrier ◽

Joint Infections ◽

Staphylococcus Capitis ◽

Prosthetic Joint ◽

Strain Collection ◽

Prosthetic Joint Infections

AbstractStaphylococcus capitis is a coagulase-negative staphylococcus that has been described primarily as causing bloodstream infections in neonatal intensive care units (NICUs), but has also recently been described in prosthetic joint infections (PJIs). The multidrug-resistant S. capitis subsp. urealyticus clone NRCS-A, comprising three sublineages, is prevalent in NICUs across the world, but its impact on other patient groups such as those suffering from PJIs or among adults planned for arthroplasty is unknown. Genome sequencing and subsequent analysis were performed on a Swedish collection of PJI isolates (n = 21), nasal commensals from patients planned to undergo arthroplasty (n = 20), NICU blood isolates (n = 9), operating theatre air isolates (n = 4), and reference strains (n = 2), in conjunction with an international strain collection (n = 248). The NRCS-A Outbreak sublineage containing the composite type V SCCmec-SCCcad/ars/cop element was present in PJIs across three Swedish hospitals. However, it was not found among nasal carrier strains, where the less virulent S. capitis subsp. capitis was most prevalent. The presence of the NRCS-A Outbreak clone in adult patients with PJIs demonstrates that dissemination occurs beyond NICUs. As this clone has several properties which facilitate invasive infections in patients with medical implants or immunosuppression, such as biofilm forming ability and multidrug resistance including heterogeneous glycopeptide-intermediate susceptibility, further research is needed to understand the reservoirs and distribution of this hospital-associated pathogen.

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