Divergent Isoprenoid Biosynthesis Pathways in Staphylococcus Species Constitute a Drug Target for Treating Infections in Companion Animals

ABSTRACT Drug-resistant Staphylococcus species are a major concern in human and veterinary medicine. There is a need for new antibiotics that exhibit a selective effect in treating infections in companion and livestock animals and that would not be used to treat human bacterial infections. We have identified fosmidomycin as an antibiotic that selectively targets certain Staphylococcus species that are often encountered in skin infections in cats and dogs. These findings expand our understanding of Staphylococcus evolution and may have direct implications for treating staphylococcal infections in veterinary medicine. Staphylococcus species are a leading cause of skin and soft tissue infections in humans and animals, and the antibiotics used to treat these infections are often the same. Methicillin- and multidrug-resistant staphylococcal infections are becoming more common in human and veterinary medicine. From a “One Health” perspective, this overlap in antibiotic use and resistance raises concerns over the potential spread of antibiotic resistance genes. Whole-genome sequencing and comparative genomics analysis revealed that Staphylococcus species use divergent pathways to synthesize isoprenoids. Species frequently associated with skin and soft tissue infections in companion animals, including S. schleiferi and S. pseudintermedius, use the nonmevalonate pathway. In contrast, S. aureus, S. epidermidis, and S. lugdunensis use the mevalonate pathway. The antibiotic fosmidomycin, an inhibitor of the nonmevalonate pathway, was effective in killing canine clinical staphylococcal isolates but had no effect on the growth or survival of S. aureus and S. epidermidis. These data identify an essential metabolic pathway in Staphylococcus that differs among members of this genus and suggest that drugs such as fosmidomycin, which targets enzymes in the nonmevalonate pathway, may be an effective treatment for certain staphylococcal infections. IMPORTANCE Drug-resistant Staphylococcus species are a major concern in human and veterinary medicine. There is a need for new antibiotics that exhibit a selective effect in treating infections in companion and livestock animals and that would not be used to treat human bacterial infections. We have identified fosmidomycin as an antibiotic that selectively targets certain Staphylococcus species that are often encountered in skin infections in cats and dogs. These findings expand our understanding of Staphylococcus evolution and may have direct implications for treating staphylococcal infections in veterinary medicine.

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Skin and Soft Tissue Infections

10.2310/em.4081 ◽

2015 ◽

Author(s):

Daniel J. Pallin

Keyword(s):

Soft Tissue ◽

Necrotizing Fasciitis ◽

Bacterial Infections ◽

Methicillin Resistant Staphylococcus Aureus ◽

Skin Infections ◽

Soft Tissue Infections ◽

Protective Mechanisms ◽

Contact Precautions ◽

Life Threatening ◽

Plantar Warts

The skin is the largest organ of the human body, and has diverse functions including protection from infection, temperature regulation, sensation, and immunologic and hormonal functions. Skin infections occur when the skin’s protective mechanisms fail. Some infections may be life-threatening (eg, necrotizing fasciitis) or may require the patient to be placed on contact precautions; thus, the initial goals of assessment of patients with skin and soft tissue infections are to assess the patient’s stability and to determine whether precautions are necessary to protect others. This review covers the pathophysiology, stabilization and assessment, diagnosis and treatment, and disposition and outcomes for a variety of skin and soft tissue infections. Figures show an algorithm for treatment of bacterial infections of the skin, and photographs of various infections including necrotizing fasciitis, cellulitis, an abscess caused by methicillin-resistant Staphylococcus aureus, a furuncle, a carbuncle, nonbullous and bullous impetigo, echythma, folliculitis, anthrax lesion, tinea corporis, condyloma acuminatum, and plantar warts. Tables list cellulitis treatment with particular exposures, the dermatophytoses, and yeast infections of skin and mucous membranes. This review contains 16 highly rendered figures, 3 tables, and 32 references.

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Antibiotics in Development for the Treatment of Resistant Bacterial Disease

Hospital Pharmacy ◽

10.1177/0018578717741393 ◽

2017 ◽

Vol 53 (1) ◽

pp. 38-40 ◽

Cited By ~ 1

Author(s):

Ryan Kidd ◽

Scot Walker

Keyword(s):

Bacterial Infections ◽

Morbidity And Mortality ◽

Bacterial Disease ◽

Drug Resistant ◽

New Antibiotics

Many bacterial infections can be treated with the use of antibiotics. These medications continue to reduce morbidity and mortality; unfortunately, their use has brought about drug-resistant pathogens that produce difficult-to-treat infections, which require more extreme treatments. New antibiotics are needed to combat this ever-evolving resistance pathogenesis.

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Comparative Analysis ofViperidaeVenoms Antibacterial Profile: a Short Communication for Proteomics

Evidence-based Complementary and Alternative Medicine ◽

10.1093/ecam/nen052 ◽

2011 ◽

Vol 2011 ◽

pp. 1-4 ◽

Cited By ~ 13

Author(s):

Bruno L. Ferreira ◽

Dilvani O. Santos ◽

André Luis dos Santos ◽

Carlos R. Rodrigues ◽

Cícero C. de Freitas ◽

...

Keyword(s):

Staphylococcus Epidermidis ◽

Bacterial Infections ◽

Multidrug Resistant ◽

Drug Resistant ◽

Future Design ◽

Important Health ◽

New Antibiotics ◽

Resistant Strains ◽

Lachesis Muta ◽

Pharmacological Potential

Bacterial infections involving multidrug-resistant strains are one of the ten leading causes of death and an important health problem in need for new antibacterial sources and agents. Herein, we tested and compared four snake venoms (Agkistrodon rhodostoma, Bothrops jararaca, B. atrox and Lachesis muta) against 10 Gram-positive and Gram-negative drug-resistant clinical bacteria strains to identify them as new sources of potential antibacterial molecules. Our data revealed that, as efficient as some antibiotics currently on the market (minimal inhibitory concentration (MIC) = 1–32 μg mL−1),A. rhodostomaandB. atroxvenoms were active againstStaphylococcus epidermidisandEnterococcus faecalis(MIC = 4.5 μg mL−1), whileB. jararacainhibitedS. aureusgrowth (MIC = 13 μg ml−1). As genomic and proteomic technologies are improving and developing rapidly, our results suggested thatA. rhodostoma, B. atroxandB. jararacavenoms and glands are feasible sources for searching antimicrobial prototypes for future design new antibiotics against drug-resistant clinical bacteria. They also point to an additional perspective to fully identify the pharmacological potential of these venoms by using different techniques.

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Aerosolized Gentamicin Reduces the Burden of Tuberculosis in a Murine Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05633-11 ◽

2011 ◽

Vol 56 (2) ◽

pp. 883-886 ◽

Cited By ~ 10

Author(s):

Chad J. Roy ◽

Satheesh K. Sivasubramani ◽

Noton K. Dutta ◽

Smriti Mehra ◽

Nadia A. Golden ◽

...

Keyword(s):

Respiratory System ◽

Murine Model ◽

Conventional Treatment ◽

Therapeutic Benefit ◽

Drug Resistant ◽

Content Type ◽

Treatment Regimes ◽

New Antibiotics ◽

Direct Delivery ◽

Major Infectious Disease

ABSTRACTTuberculosis (TB) is a major infectious disease problem: 1.7 million people annually die due to TB. Emergence of drug-resistantMycobacterium tuberculosisand the lack of new antibiotics have exacerbated the situation. There is an urgent need to develop or repurpose drugs against TB. We evaluated inhaled gentamicin as direct respiratory system-targeted therapy in a murine model of TB. Aerosolized-gentamicin-treated mice showed significantly reduced lungM. tuberculosisloads and fewer granulomas relative to untreated controls. These results suggest that direct delivery of antibiotics to the respiratory system may provide therapeutic benefit to conventional treatment regimes for treatment of pulmonary TB.

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Fosfomycin

Clinical Microbiology Reviews ◽

10.1128/cmr.00068-15 ◽

2016 ◽

Vol 29 (2) ◽

pp. 321-347 ◽

Cited By ~ 193

Author(s):

Matthew E. Falagas ◽

Evridiki K. Vouloumanou ◽

George Samonis ◽

Konstantinos Z. Vardakas

Keyword(s):

Bacterial Infections ◽

Clinical Effectiveness ◽

Multidrug Resistant ◽

Resistant Bacteria ◽

Drug Resistant ◽

Antibiotic Resistant ◽

Development Of Resistance ◽

Extensively Drug Resistant ◽

New Antibiotics

SUMMARYThe treatment of bacterial infections suffers from two major problems: spread of multidrug-resistant (MDR) or extensively drug-resistant (XDR) pathogens and lack of development of new antibiotics active against such MDR and XDR bacteria. As a result, physicians have turned to older antibiotics, such as polymyxins, tetracyclines, and aminoglycosides. Lately, due to development of resistance to these agents, fosfomycin has gained attention, as it has remained active against both Gram-positive and Gram-negative MDR and XDR bacteria. New data of higher quality have become available, and several issues were clarified further. In this review, we summarize the available fosfomycin data regarding pharmacokinetic and pharmacodynamic properties, thein vitroactivity against susceptible and antibiotic-resistant bacteria, mechanisms of resistance and development of resistance during treatment, synergy and antagonism with other antibiotics, clinical effectiveness, and adverse events. Issues that need to be studied further are also discussed.

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Efficacy of OH-CATH30 and Its Analogs against Drug-Resistant BacteriaIn Vitroand in Mouse Models

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.06304-11 ◽

2012 ◽

Vol 56 (6) ◽

pp. 3309-3317 ◽

Cited By ~ 38

Author(s):

Sheng-An Li ◽

Wen-Hui Lee ◽

Yun Zhang

Keyword(s):

Mouse Models ◽

Bacterial Infections ◽

Resistant Bacteria ◽

Infection Model ◽

Drug Resistant ◽

Content Type ◽

E Coli ◽

Drug Resistant Bacteria

ABSTRACTAntimicrobial peptides (AMPs) have been considered alternatives to conventional antibiotics for drug-resistant bacterial infections. However, their comparatively high toxicity toward eukaryotic cells and poor efficacyin vivohamper their clinical application. OH-CATH30, a novel cathelicidin peptide deduced from the king cobra, possesses potent antibacterial activityin vitro. The objective of this study is to evaluate the efficacy of OH-CATH30 and its analog OH-CM6 against drug-resistant bacteriain vitroandin vivo. The MICs of OH-CATH30 and OH-CM6 ranged from 1.56 to 12.5 μg/ml against drug-resistant clinical isolates of several pathogenic species, includingEscherichia coli,Pseudomonas aeruginosa, and methicillin-resistantStaphylococcus aureus. The MICs of OH-CATH30 and OH-CM6 were slightly altered in the presence of 25% human serum. OH-CATH30 and OH-CM6 killedE. coliquickly (within 60 min) by disrupting the bacterial cytoplasmic membrane. Importantly, the 50% lethal doses (LD50) of OH-CATH30 and OH-CM6 in mice following intraperitoneal (i.p.) injection were 120 mg/kg of body weight and 100 mg/kg, respectively, and no death was observed at any dose up to 160 mg/kg following subcutaneous (s.c.) injection. Moreover, 10 mg/kg OH-CATH30 or OH-CM6 significantly decreased the bacterial counts as well as the inflammatory response in a mouse thigh infection model and rescued infected mice in a bacteremia model induced by drug-resistantE. coli. Taken together, our findings demonstrate that the natural cathelicidin peptide OH-CATH30 and its analogs exhibit relatively low toxicity and potent efficacy in mouse models, indicating that they may have therapeutic potential against the systemic infections caused by drug-resistant bacteria.

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Ceftolozane-Tazobactam Activity against Pseudomonas aeruginosa Clinical Isolates from U.S. Hospitals: Report from the PACTS Antimicrobial Surveillance Program, 2012 to 2015

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00465-17 ◽

2017 ◽

Vol 61 (7) ◽

Cited By ~ 40

Author(s):

Dee Shortridge ◽

Mariana Castanheira ◽

Michael A. Pfaller ◽

Robert K. Flamm

Keyword(s):

Pseudomonas Aeruginosa ◽

Bacterial Infections ◽

Multidrug Resistant ◽

Surveillance Program ◽

Drug Resistant ◽

Content Type ◽

Microdilution Method ◽

Antimicrobial Surveillance ◽

Broth Microdilution Method

ABSTRACT The activity of ceftolozane-tazobactam was compared to the activities of 7 antimicrobials against 3,851 Pseudomonas aeruginosa isolates collected from 32 U.S. hospitals in the Program to Assess Ceftolozane-Tazobactam Susceptibility from 2012 to 2015. Ceftolozane-tazobactam and comparator susceptibilities were determined using the CLSI broth microdilution method at a central monitoring laboratory. For ceftolozane-tazobactam, 97.0% of the isolates were susceptible. Susceptibilities of the other antibacterials tested were: amikacin, 96.9%; cefepime, 85.9%; ceftazidime, 85.1%; colistin, 99.2%; levofloxacin, 76.6%; meropenem, 81.8%; and piperacillin-tazobactam, 80.4%. Of the 699 (18.1%) meropenem-nonsusceptible P. aeruginosa isolates, 87.6% were susceptible to ceftolozane-tazobactam. Six hundred seven isolates (15.8%) were classified as multidrug resistant (MDR), and 363 (9.4%) were classified as extensively drug resistant (XDR). Only 1 isolate was considered pandrug resistant, which was resistant to all tested agents, including colistin. Of the 607 MDR isolates, 84.9% were ceftolozane-tazobactam susceptible, and 76.9% of XDR isolates were ceftolozane-tazobactam susceptible. In vitro activity against drug-resistant P. aeruginosa indicates ceftolozane-tazobactam may be an important agent in treating serious bacterial infections.

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Efficacy of Lantibiotic Treatment of Staphylococcus aureus-Induced Skin Infections, Monitored byIn VivoBioluminescent Imaging

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02938-15 ◽

2016 ◽

Vol 60 (7) ◽

pp. 3948-3955 ◽

Cited By ~ 21

Author(s):

Anton Du Preez van Staden ◽

Tiaan Heunis ◽

Carine Smith ◽

Shelly Deane ◽

Leon M. T. Dicks

Keyword(s):

Staphylococcus Aureus ◽

Soft Tissue ◽

Treatment Options ◽

Bacterial Pathogen ◽

Antimicrobial Activities ◽

Skin Infections ◽

Soft Tissue Infections ◽

Content Type ◽

Alternative Treatment Option

ABSTRACTStaphylococcus aureusis a bacterial pathogen responsible for the majority of skin and soft tissue infections. Antibiotics are losing their efficacy as treatment for skin and soft tissue infections as a result of increased resistance in a variety of pathogens, includingS. aureus. It is thus imperative to explore alternative antimicrobial treatments to ensure future treatment options for skin and soft tissue infections. A select few lantibiotics, a group of natural defense peptides produced by bacteria, inhibit the growth of numerous clinicalS. aureusisolates, including methicillin-resistant strains. In this study, the antimicrobial activities of nisin, clausin, and amyloliquecidin, separately administered, were compared to that of a mupirocin-based ointment, which is commonly used as treatment forS. aureus-induced skin infections. Full-thickness excisional wounds, generated on the dorsal surfaces of mice, were infected with a bioluminescent strain ofS. aureus(strain Xen 36). The infections were monitored in real time usingin vivobioluminescent imaging. Lantibiotic treatments significantly reduced the bioluminescence ofS. aureusXen 36 to a level similar to that recorded with mupirocin treatment. Wound closure, however, was more pronounced during lantibiotic treatment. Lantibiotics thus have the potential to be used as an alternative treatment option forS. aureus-induced skin infections.

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Aminomethyl Spectinomycins as Therapeutics for Drug-Resistant Gonorrhea and Chlamydia Coinfections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00325-18 ◽

2018 ◽

Vol 62 (5) ◽

Cited By ~ 11

Author(s):

Michelle M. Butler ◽

Samanthi L. Waidyarachchi ◽

Kristie L. Connolly ◽

Ann E. Jerse ◽

Weirui Chai ◽

...

Keyword(s):

Bacterial Species ◽

New Drugs ◽

Drug Resistant ◽

Content Type ◽

Sexually Transmitted ◽

Recommended Treatment ◽

New Antibiotics ◽

Added Benefit ◽

Study Support

ABSTRACTBacterial sexually transmitted infections are widespread and common, withNeisseria gonorrhoeae(gonorrhea) andChlamydia trachomatis(chlamydia) being the two most frequent causes. If left untreated, both infections can cause pelvic inflammatory disease, infertility, ectopic pregnancy, and other sequelae. The recommended treatment for gonorrhea is ceftriaxone plus azithromycin (to empirically treat chlamydial coinfections). Antibiotic resistance to all existing therapies has developed in gonorrheal infections. The need for new antibiotics is great, but the pipeline for new drugs is alarmingly small. The aminomethyl spectinomycins, a new class of semisynthetic analogs of the antibiotic spectinomycin, were developed on the basis of a computational analysis of the spectinomycin binding site of the bacterial 30S ribosome and structure-guided synthesis. The compounds display particular potency against common respiratory tract pathogens as well as the sexually transmitted pathogens that cause gonorrhea and chlamydia. Here, we demonstrate thein vitropotencies of several compounds of this class against both bacterial species; the compounds displayed increased potencies againstN. gonorrhoeaecompared to that of spectinomycin and, significantly, demonstrated activity againstC. trachomatisthat is not observed with spectinomycin. Efficacies of the compounds were compared to those of spectinomycin and gentamicin in a murine model of infection caused by ceftriaxone/azithromycin-resistantN. gonorrhoeae; the aminomethyl spectinomycins significantly reduced the colonization load and were as potent as the comparator compounds. In summary, data produced by this study support aminomethyl spectinomycins as a promising replacement for spectinomycin and antibiotics such as ceftriaxone for treating drug-resistant gonorrhea, with the added benefit of treating chlamydial coinfections.

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A Dimer, but Not Monomer, of Tobramycin Potentiates Ceftolozane against Multidrug-Resistant and Extensively Drug-Resistant Pseudomonas aeruginosa and Delays Resistance Development

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02055-19 ◽

2020 ◽

Vol 64 (3) ◽

Cited By ~ 4

Author(s):

Temilolu Idowu ◽

George G. Zhanel ◽

Frank Schweizer

Keyword(s):

Pseudomonas Aeruginosa ◽

Bacterial Infections ◽

Multidrug Resistant ◽

Drug Resistant ◽

Content Type ◽

Extensively Drug Resistant ◽

In The Wild ◽

Tract Infections ◽

Hospital Acquired

ABSTRACT Ceftolozane-tazobactam is a potent β-lactam/β-lactamase inhibitor combination approved for the treatment of complicated intraabdominal and complicated urinary tract infections and, more recently, the treatment of hospital-acquired and ventilator-associated bacterial pneumonia. Although the activities of ceftolozane are not enhanced by tazobactam against Pseudomonas aeruginosa, it remains the most potent antipseudomonal agent approved to date. Emerging data worldwide has included reports of microbiological failure in patients with serious bacterial infections caused by multidrug-resistant (MDR) P. aeruginosa as a result of ceftolozane resistance developed within therapy. The objective of this study is to compare the efficacy of a tobramycin homodimer plus ceftolozane versus ceftolozane-tazobactam alone against MDR and extensively drug-resistant (XDR) P. aeruginosa. Tobramycin homodimer, a synthetic dimer of two monomeric units of tobramycin, was developed to abrogate the ribosomal properties of tobramycin with a view to mitigating aminoglycoside-related toxicity and resistance. Herein, we report that tobramycin homodimer, a nonribosomal aminoglycoside derivative, potentiates the activities of ceftolozane versus MDR/XDR P. aeruginosa in vitro and delays the emergence of resistance to ceftolozane-tazobactam in the wild-type PAO1 strain. This combination is also more potent than a standard ceftazidime-avibactam combination against these isolates. Conversely, a tobramycin monomer with intrinsic ribosomal properties does not potentiate ceftolozane under similar conditions. Susceptibility and checkerboard studies were assessed using serial 2-fold dilution assays, following the Clinical and Laboratory Standards Institute (CLSI) guidelines. This strategy provides an avenue to further preserve the clinical utility of ceftolozane and enhances its spectrum of activity against one of the most difficult-to-treat pathogens in hospitals.

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