Identification and evolution of ICE-PmuST394: a novel integrative conjugative element in Pasteurella multocida ST394.

BACKGROUND: The emergence of macrolide and tetracycline resistance within Pasteurella multocida isolated from feedlot cattle and the dominance of ST394 in Australia was reported recently. OBJECTIVES: To establish the genetic context of the resistance genes in P. multocida 17BRD-035, the ST394 reference genome, and conduct a molecular risk assessment of their ability to disperse laterally. METHODS: A bioinformatic analysis of the P. multocida 17BRD-035 genome was conducted to determine if integrative conjugative elements (ICEs) carrying resistance genes, which hamper antibiotic treatment options locally, are in circulation in Australian feedlots. RESULTS: A novel element, ICE-PmuST394, was characterized in P. multocida 17BRD-035. It was also identified in three other isolates (two ST394s and a ST125) in Australia and is likely present in a genome representing P. multocida ST79 from the USA. ICE-PmuST394 houses a resistance module carrying two variants of the blaROB gene, blaROB-1 and blaROB-13, and the macrolide esterase gene, estT. The resistance gene combination on ICE-PmuST394 confers resistance to ampicillin and tilmicosin, but not to tulathromycin and tildipirosin. Our analysis suggests that ICE-PmuST394 is circulating both by clonal expansion and horizontal transfer but is currently restricted to a single feedlot in Australia. CONCLUSIONS: ICE-PmuST394 carries a limited number of unusual antimicrobial resistance genes but has hotspots that facilitate genomic recombination. The element is therefore amenable to hosting more resistance genes, and therefore its presence (or dispersal) should be regularly monitored. The element has a unique molecular marker, which could be exploited for genomic surveillance purposes locally and globally.

Oral administration of a 2-aminopyrimidine robenidine analogue (NCL195) significantly reduces Staphylococcus aureus infection and reduces Escherichia coli infection in combination with sub-inhibitory colistin concentrations in a bioluminescent mouse model.

We have previously reported promising in vivo activity of the first-generation 2-aminopyramidine robenidine analogue NCL195 against Gram-positive bacteria (GPB) when administered via the systemic route. In this study, we examined the efficacy of oral treatment with NCL195 (± low-dose colistin) in comparison to oral moxifloxacin in bioluminescent Staphylococcus aureus and Escherichia coli peritonitis-sepsis models. Four oral doses of 50 mg/kg NCL195, commencing immediately post-infection, were administered at 4 h intervals in the S. aureus peritonitis-sepsis model. We used a combination of four oral doses of 50 mg/kg NCL195 and four intraperitoneal doses of colistin at 0.125 mg/kg, 0.25 mg/kg, or 0.5 mg/kg in the E. coli peritonitis-sepsis model. Subsequently, the dose rates of four intraperitoneal doses of colistin were increased to 0.5 mg/kg, 1 mg/kg, or 2 mg/kg at 4 h intervals to treat a colistin-resistant E. coli infection. In the S. aureus infection model, oral treatment of mice with NCL195 resulted in significantly reduced S. aureus infection loads (P < 0.01) and longer survival times (P < 0.001) than vehicle-only treated mice. In the E. coli infection model, co-administration of NCL195 and graded doses of colistin resulted in a dose-dependent significant reduction in colistin-susceptible (P < 0.01) or colistin-resistant (P < 0.05) E. coli loads compared to treatment with colistin alone at similar concentrations. Our results confirm that NCL195 is a potential candidate for further preclinical development as a specific treatment for multidrug-resistant infections, either as a stand-alone antibiotic for GPB or in combination with sub-inhibitory concentrations of colistin for Gram-negative bacteria.

Impact of the new membrane-targeting lipoglycopeptide antibiotic MCC5145 on the treatment of bacteremic pneumococcal pneumonia in mice.

Bacteremic Streptococcus pneumoniae pneumonia is one of the most severe forms of invasive pneumococcal disease (IPD) and with particularly high case-fatality rates among the elderly and individuals with comorbidities, exacerbated by rising antibiotic resistance and time to initiation of therapy. Here, we examined the efficacy of the preclinical "vancapticin" glycopeptide MCC5145 against fulminant infection by S. pneumoniae serotype 2 strain D39 in a bioluminescent, neutropenic mouse model of bacteremic pneumonia. MCC5145 is a semisynthetic vancomycin derivative chemically modified at the C-terminus with a membrane-targeting motif designed to preferentially bind the anionic bacterial surface. We show that similar to vancomycin, subcutaneous administration of MCC5145 to mice 1 day after intranasal infection with a bioluminescent derivative of S. pneumoniae D39 elicited time and concentration-dependent reduction in total flux in the lungs and blood. Together, our finding supports the further development of MCC5145 as a potential new treatment option for pneumonia and/or bacteremic pneumonia in clinical settings, particularly for immunocompromised individuals. IMPORTANCE S. pneumoniae (the pneumococcus) causes severe community acquired lung and blood infection, especially among the elderly and people with underlying medical conditions and/or weakened immune systems. The rising incidence of antibiotic resistance and delays between diagnosis of infection and commencement of effective therapy make treatment difficult and result in high mortality rates. In this work, we show that a new derivative (MCC5145) of an existing antibiotic (vancomycin) rapidly eradicated lethal pneumococcal challenge from the lungs and blood of mice with a suppressed immune system. Our findings support that MCC5145 is a promising option for the treatment of lung and blood infections caused by the pneumococcus at point-of-care settings, particularly for the elderly and individuals with a weakened immune system.

Correction: Messele et al. Longitudinal Analysis of Antimicrobial Resistance among Enterococcus Species Isolated from Australian Beef Cattle Faeces at Feedlot Entry and Exit. Animals 2022, 12, 2690.

There was an error in the original publication [...].

Nanotechnology and narasin: a powerful combination against acne.

Acne vulgaris is widely regarded as the most prevalent skin disorder characterized by painful, inflammatory skin lesions that are primarily attributed to the pathogenic actions of Cutibacterium acnes (C. acnes). To improve the clinical management of this disease, there is a pressing clinical demand to develop innovative antibacterial therapies that utilize novel mechanisms. The current research aimed to discover the antibacterial efficacy of narasin (NAR), a polyether ionophore, against drug-resistant acne bacteria. In addition, the study aimed to formulate self-nanomicellizing solid dispersions (SNMSD), utilizing Soluplus® (SOL), as a drug delivery system to incorporate NAR and selectively target the lipophilic C. acnes abundant environments within the skin. Furthermore, the study aimed to investigate the ex vivo deposition and permeation of NAR into the various layers of the skin using full-thickness porcine ear skin as a model skin. By encapsulating NAR within spherical polymeric micelles (dn < 80 nm) aqueous solubility was significantly increased by approximately 100-fold (from <40 µg mL-1 to 4600 µg mL-1). Following optimization, the micelle solution was integrated into a gel formulation (containing 0.2% w/v NAR) and evaluated for stability over 4 weeks at room temperature (drug content >98%). Results from drug deposition and permeation experiments demonstrated that the deposition of NAR from the NAR-micelle solution and its gel formulation into the lipophilic stratum corneum (19 835.60 ± 6237.89 ng cm-2 and 40 601.14 ± 3736.09 ng cm-2) and epidermis (19 347 ± 1912.98 ng cm-2 and 18 763.54 ± 580.77 ng cm-2) was superior to that of NAR in solution, which failed to penetrate any skin layers. In conclusion, the outcomes of this study provide evidence that NAR exhibits promising activity against antimicrobial resistant strains of C. acnes (MIC range ≤0.008-0.062) and that micelle nanocarriers can improve the aqueous solubility of poorly water-soluble drugs. Furthermore, our results highlight the ability of nanomicelles to enable selective and targeted drug delivery to the lipophilic skin layers.

Phylogeny, Virulence, and Antimicrobial Resistance Gene Profiles of Enterococcus faecium Isolated from Australian Feedlot Cattle and Their Significance to Public and Environmental Health.

The extent of similarity between E. faecium strains found in healthy feedlot beef cattle and those causing extraintestinal infections in humans is not yet fully understood. This study used whole-genome sequencing to analyse the antimicrobial resistance profile of E. faecium isolated from beef cattle (n = 59) at a single feedlot and compared them to previously reported Australian isolates obtained from pig (n = 60) and meat chicken caecal samples (n = 8), as well as human sepsis cases (n = 302). The E. faecium isolated from beef cattle and other food animal sources neither carried vanA/vanB responsible for vancomycin nor possessed gyrA/parC and liaR/liaS gene mutations associated with high-level fluoroquinolone and daptomycin resistance, respectively. A small proportion (7.6%) of human isolates clustered with beef cattle and pig isolates, including a few isolates belonging to the same sequence types ST22 (one beef cattle, one pig, and two human isolates), ST32 (eight beef cattle and one human isolate), and ST327 (two beef cattle and one human isolate), suggesting common origins. This provides further evidence that these clonal lineages may have broader host range but are unrelated to the typical hospital-adapted human strains belonging to clonal complex 17, significant proportions of which contain vanA/vanB and liaR/liaS. Additionally, none of the human isolates belonging to these STs contained resistance genes to WHO critically important antimicrobials. The results confirm that most E. faecium isolated from beef cattle in this study do not pose a significant risk for resistance to critically important antimicrobials and are not associated with current human septic infections.

Dominance of Escherichia coli sequence types ST73, ST95, ST127 and ST131 in Australian urine isolates: a genomic analysis of antimicrobial resistance and virulence linked to F plasmids.

Extraintestinal pathogenic Escherichia coli (ExPEC) are the most frequent cause of urinary tract infections (UTIs) globally. Most studies of clinical E. coli isolates are selected based on their antimicrobial resistance (AMR) phenotypes; however, this selection bias may not provide an accurate portrayal of which sequence types (STs) cause the most disease. Here, whole genome sequencing (WGS) was performed on 320 E. coli isolates from urine samples sourced from a regional hospital in Australia in 2006. Most isolates (91%) were sourced from patients with UTIs and were not selected based on any AMR phenotypes. No significant differences were observed in AMR and virulence genes profiles across age sex, and uro-clinical syndromes. While 88 STs were identified, ST73, ST95, ST127 and ST131 dominated. F virulence plasmids carrying senB-cjrABC (126/231; 55%) virulence genes were a feature of this collection. These senB-cjrABC+ plasmids were split into two categories: pUTI89-like (F29:A-:B10 and/or >95 % identity to pUTI89) (n=73) and non-pUTI89-like (n=53). Compared to all other plasmid replicons, isolates with pUTI89-like plasmids carried fewer antibiotic resistance genes (ARGs), whilst isolates with senB-cjrABC+/non-pUTI89 plasmids had a significantly higher load of ARGs and class 1 integrons. F plasmids were not detected in 89 genomes, predominantly ST73. Our phylogenomic analyses identified closely related isolates from the same patient associated with different pathologies and evidence of strain-sharing events involving isolates sourced from companion and wild animals.

Gut Microbiota and Behavioural Issues in Production, Performance, and Companion Animals: A Systematic Review.

The literature has identified poor nutrition as the leading factor in the manifestation of many behavioural issues in animals, including aggression, hyperalertness, and stereotypies. Literature focused on all species of interest consistently reported that although there were no significant differences in the richness of specific bacterial taxa in the microbiota of individual subjects with abnormal behaviour (termed alpha diversity), there was variability in species diversity between these subjects compared to controls (termed beta diversity). As seen in humans with mental disorders, animals exhibiting abnormal behaviour often have an enrichment of pro-inflammatory and lactic acid-producing bacteria and a reduction in butyrate-producing bacteria. It is evident from the literature that an association exists between gut microbiota diversity (and by extension, the concurrent production of microbial metabolites) and abnormal behavioural phenotypes across various species, including pigs, dogs, and horses. Similar microbiota population changes are also evident in human mental health patients. However, there are insufficient data to identify this association as a cause or effect. This review provides testable hypotheses for future research to establish causal relationships between gut microbiota and behavioural issues in animals, offering promising potential for the development of novel therapeutic and/or preventative interventions aimed at restoring a healthy gut-brain-immune axis to mitigate behavioural issues and, in turn, improve health, performance, and production in animals.

Genomic profiling of Pasteurella multocida isolated from feedlot cases of bovine respiratory disease.

Pasteurella multocida causes a range of diseases in many host species throughout the world, including bovine respiratory disease (BRD) which is predominantly seen in feedlot cattle. This study assessed genetic diversity among 139 P. multocida isolates obtained from post-mortem lung swabs of BRD-affected feedlot cattle in four Australian states: New South Wales, Queensland, South Australia, and Victoria during 2014-2019. Whole-genome sequencing (WGS) was used to determine capsular serogroup, lipopolysaccharide genotypes, multi-locus sequence types and phylogenetic relationships. Two capsular types (A and D), with most isolates (132/139; 95%) belonging to type A; and three lipopolysaccharide (LPS) genotypes were identified (L1 [6/139; 4.3%], L3 [124/139; 89.2%] and L6 [9/139; 6.4%)]). Multi-locus sequence types (STs) ST9, ST13, ST17, ST20, ST36, ST50, ST58, ST79, ST124, ST125, ST132, ST167, ST185, ST327, ST394, and three novel STs [ST396, ST397, and ST398] were identified, with ST394 (59/139; 42.4%) and ST79 (44/139; 32%) the most prevalent in all four states. Isolates displaying phenotypic resistance to single, dual or multiple antibiotics (macrolide, tetracycline and aminopenicillins) were predominantly ST394 (23/139; 17%). Laterally mobile elements identified in the resistant ST394 isolates included small plasmids, encoding macrolide and/or tetracycline resistance, distributed in all states; and chromosomally located integrative conjugative elements (ICEs) (4 ST394 and 1 ST125) from the same Queensland feedlot. This study highlights the genomic diversity, epidemiological relationships and AMR associations in bovine P. multocida isolates from Australia and provides insight into the unique ST prevalence compared to other major beef-producing countries.

Antimicrobial susceptibility and molecular characteristics of Mycoplasma bovis isolated from cases of bovine respiratory disease in Australian feedlot cattle.

To date, antimicrobial susceptibility has not been reported for Australian Mycoplasma bovis isolates. This study determined minimal inhibitory concentrations (MICs) for 12 different antimicrobials against Australian M. bovis isolates and used whole genome sequencing to screen those showing high macrolide MICs for point mutations in target genes. Most lung tissue/swab samples from bovine respiratory disease cases (61/76, 80.3%) tested positive for M. bovis. A set of 50 representative isolates (50/61, 82.0%) that showed adequate growth, was used for MIC testing. Uniformly, low MIC values were confirmed for enrofloxacin (≤ 4 µg/mL), florfenicol (≤ 8 µg/mL), gamithromycin (≤ 2 µg/mL), spectinomycin (≤ 4 µg/mL), tetracycline (≤ 8 µg/mL), tiamulin (≤ 4 µg/mL), and tulathromycin (≤ 0.5 µg/mL). A small proportion (10%) of isolates exhibited high MICs (≥ 32 µg/mL) for tildipirosin, tilmicosin, tylosin, and lincomycin, which were above the epidemiological cut-off values for each antimicrobial (≥ 4 µg/mL). These isolates, originating from three Australian states, underwent whole genome sequencing/multilocus sequencing typing and were compared with the reference strain PG45 to investigate mutations that might be linked with the high macrolide/lincosamide MICs. All five belonged to ST52 and two macrolide associated mutations were identified within the 23 S rRNA gene (A2058G in two sequenced isolates and G748A in all sequenced isolates). Four additional 23 S rRNA gene mutations did not appear to be linked to macrolide resistance. Whilst the majority of Australian M. bovis isolates appear susceptible to the tested antimicrobials, emerging macrolide resistance was detected in three Australian states and requires continued monitoring.

Phylogenetic Analysis of Escherichia coli Isolated from Australian Feedlot Cattle in Comparison to Pig Faecal and Poultry/Human Extraintestinal Isolates.

The similarity of commensal Escherichia coli isolated from healthy cattle to antimicrobial-resistant bacteria causing extraintestinal infections in humans is not fully understood. In this study, we used a bioinformatics approach based on whole genome sequencing data to determine the genetic characteristics and phylogenetic relationships among faecal Escherichia coli isolates from beef cattle (n = 37) from a single feedlot in comparison to previously analysed pig faecal (n = 45), poultry extraintestinal (n = 19), and human extraintestinal E. coli isolates (n = 40) from three previous Australian studies. Most beef cattle and pig isolates belonged to E. coli phylogroups A and B1, whereas most avian and human isolates belonged to B2 and D, although a single human extraintestinal isolate belonged to phylogenetic group A and sequence type (ST) 10. The most common E. coli sequence types (STs) included ST10 for beef cattle, ST361 for pig, ST117 for poultry, and ST73 for human isolates. Extended-spectrum and AmpC ß-lactamase genes were identified in seven out of thirty-seven (18.9%) beef cattle isolates. The most common plasmid replicons identified were IncFIB (AP001918), followed by IncFII, Col156, and IncX1. The results confirm that feedlot cattle isolates examined in this study represent a reduced risk to human and environmental health with regard to being a source of antimicrobial-resistant E. coli of clinical importance.

Identification of genes influencing the evolution of Escherichia coli ST372 in dogs and humans.

ST372 are widely reported as the major Escherichia coli sequence type in dogs globally. They are also a sporadic cause of extraintestinal infections in humans. Despite this, it is unknown whether ST372 strains from dogs and humans represent shared or distinct populations. Furthermore, little is known about genomic traits that might explain the prominence of ST372 in dogs or presence in humans. To address this, we applied a variety of bioinformatics analyses to a global collection of 407 ST372 E. coli whole-genome sequences to characterize their epidemiological features, population structure and associated accessory genomes. We confirm that dogs are the dominant host of ST372 and that clusters within the population structure exhibit distinctive O:H types. One phylogenetic cluster, 'cluster M', comprised almost half of the sequences and showed the divergence of two human-restricted clades that carried different O:H types to the remainder of the cluster. We also present evidence supporting transmission between dogs and humans within different clusters of the phylogeny, including M. We show that multiple acquisitions of the pdu propanediol utilization operon have occurred in clusters dominated by isolates of canine source, possibly linked to diet, whereas loss of the pdu operon and acquisition of K antigen virulence genes characterize human-restricted lineages.

In Vitro Activity of Robenidine Analogues NCL259 and NCL265 against Gram-Negative Pathogens.

Multidrug-resistant (MDR) Gram-negative pathogens, especially Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli and Enterobacter spp., are recognized by the World Health Organization as the most critical priority pathogens in urgent need of drug development. In this study, the in vitro antimicrobial activity of robenidine analogues NCL259 and NCL265 was tested against key human and animal Gram-negative clinical isolates and reference strains. NCL259 and NCL265 demonstrated moderate antimicrobial activity against these Gram-negative priority pathogens with NCL265 consistently more active, achieving lower minimum inhibitory concentrations (MICs) in the range of 2−16 µg/mL. When used in combination with sub-inhibitory concentrations of polymyxin B to permeabilize the outer membrane, NCL259 and NCL265 elicited a synergistic or additive activity against the reference strains tested, reducing the MIC of NCL259 by 8- to 256- fold and the MIC of NCL265 by 4- to 256- fold. A small minority of Klebsiella spp. isolates (three) were resistant to both NCL259 and NCL265 with MICs > 256 µg/mL. This resistance was completely reversed in the presence of the efflux pump inhibitor phenylalanine-arginine-beta-naphthylamide (PAßN) to yield MIC values of 8−16 µg/mL and 2−4 µg/mL for NCL259 and NCL256, respectively. When NCL259 and NCL265 were tested against wild-type E. coli isolate BW 25113 and its isogenic multidrug efflux pump subunit AcrB deletion mutant (∆AcrB), the MIC of both compounds against the mutant ∆AcrB isolate was reduced 16-fold compared to the wild-type parent, indicating a significant role for the AcrAB-TolC efflux pump from Enterobacterales in imparting resistance to these robenidine analogues. In vitro cytotoxicity testing revealed that NCL259 and NCL265 had much higher levels of toxicity to a range of human cell lines compared to the parent robenidine, thus precluding their further development as novel antibiotics against Gram-negative pathogens.

Longitudinal Analysis of Antimicrobial Resistance among Enterococcus Species Isolated from Australian Beef Cattle Faeces at Feedlot Entry and Exit.

Enterococcus faecium are commensal bacteria inhabiting the gastrointestinal tract of animals and humans and an important cause of drug-resistant nosocomial infections. This longitudinal study aimed to determine whether changes in the antimicrobial resistance (AMR) phenotype and genotype occurred among Enterococcus spp. isolated from cattle rectal samples obtained at the entry to and exit from an Australian feedlot. The samples obtained at the feedlot induction yielded enterococci (104/150; 69.3%), speciated as E. hirae (90/104; 86.5%), E. faecium (9/104; 8.7%), E. mundtii (3/104; 2.9%), E. durans, and E. casseliflavus (1/104; 1.0% each). AMR was observed to lincomycin (63/104; 60.6%), daptomycin (26/104; 25.0%), nitrofurantoin (9/104; 8.7%), ciprofloxacin (7/104; 6.7%), tetracycline (5/104; 4.8%), tigecycline (4/104; 3.9%), and quinupristin/dalfopristin (3/104; 2.9%). From the rectal swab samples collected at the abattoir from the same animals (i.e., the feedlot exit), the enterococci recovery was significantly higher (144/150; 96.0%), with a marked shift in species distribution dominated by E. faecium (117/144; 81.3%). However, the prevalence of AMR to individual antimicrobials remained largely static between the entry and exit except for the increased resistance to nitrofurantoin (77/144; 53.5%) and quinupristin/dalfopristin (26/144; 18.1%). Overall, 13 AMR genes were observed among the 62 E. faecium isolates. These included aac(6')Ii, aac(6')-Iid, and ant(6)-Ia (aminoglycosides); eatAv, lnu(G), vat(E), msr(C), and erm(B) (macrolides, lincosamides, and streptogramins); efmA (fluoroquinolones); and tet(45), tet(L), tet(M), and tet(S) (tetracyclines). The results confirm the presence of fluoroquinolone- and streptogramin-resistant enterococci in cattle faeces at the feedlot entry in the absence of antimicrobial selection pressure. E. faecium, exhibiting increased nitrofurantoin resistance, became the dominant Enterococcus spp. during the feeding period.

Phenotypic and Genotypic Analysis of Antimicrobial Resistance in Escherichia coli Recovered from Feedlot Beef Cattle in Australia.

This study investigated the antimicrobial resistance (AMR) profile of fecal Escherichia coli isolates from beef cattle (n = 150) at entry and exit from an Australian feedlot. Sample plating on MacConkey agar and Brilliance ESBL agar differentiated generic from extended-spectrum ß-lactamase (ESBL)-producing E. coli, respectively. Resistance profiles were determined by minimum inhibitory concentration (MIC) testing and further analyzed by whole-genome sequencing (WGS). At entry, the prevalence of antimicrobial resistance to amoxicillin/clavulanic acid, ampicillin, streptomycin, and trimethoprim/sulfamethoxazole was very low (0.7%, each). At the exit, the resistance prevalence was moderate to tetracycline (17.8%) and low to ampicillin (5.4%), streptomycin (4.7%), and sulfisoxazole (3.9%). The most common AMR genes observed in phenotypically resistant isolates were tet(B) (43.2%), aph(3″)-Ib and aph(6)-Id (32.4%), blaTEM-1B, and sul2 (24.3%, each), which are responsible for resistance to tetracyclines, aminoglycosides, ß-lactams, and sulfonamides, respectively. The ESBL-producing E. coli were recovered from one sample (0.7%) obtained at entry and six samples (4.0%) at the exit. The ESBL-producing E. coli harbored blaTEM (29.7%), blaCTX m(13.5%), and blaCMY (5.4%). The resistance phenotypes were highly correlated with resistance genotypes (r ≥ 0.85: p < 0.05). This study demonstrated that E. coli isolated from feedlot beef cattle can harbour AMR genes, but the low incidence of medically important resistance reflected the prudent antimicrobial use in the Australian industry.

A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections.

Drug-resistant Gram-positive bacterial infections are still a substantial burden on the public health system, with two bacteria (Staphylococcus aureus and Streptococcus pneumoniae) accounting for over 1.5 million drug-resistant infections in the United States alone in 2017. In 2019, 250,000 deaths were attributed to these pathogens globally. We have developed a preclinical glycopeptide antibiotic, MCC5145, that has excellent potency (MIC90 ≤ 0.06 µg/ml) against hundreds of isolates of methicillin-resistant S. aureus (MRSA) and other Gram-positive bacteria, with a greater than 1000-fold margin over mammalian cell cytotoxicity values. The antibiotic has therapeutic in vivo efficacy when dosed subcutaneously in multiple murine models of established bacterial infections, including thigh infection with MRSA and blood septicemia with S. pneumoniae, as well as when dosed orally in an antibiotic-induced Clostridioides difficile infection model. MCC5145 exhibited reduced nephrotoxicity at microbiologically active doses in mice compared to vancomycin. MCC5145 also showed improved activity against biofilms compared to vancomycin, both in vitro and in vivo, and a low propensity to select for drug resistance. Characterization of drug action using a transposon library bioinformatic platform showed a mechanistic distinction from other glycopeptide antibiotics.

Antimicrobial susceptibility and genomic analysis of Histophilus somni isolated from cases of bovine respiratory disease in Autralian feedlot cattle.

Histophilus somni is a prevalent commensal organism of the upper respiratory tract of cattle and a major causative agent of bovine respiratory disease (BRD) and other syndromes including myocarditis and infectious thromboembolic meningoencephalitis. This study investigated the antimicrobial susceptibility and phylogenetic relationships of H. somni isolates obtained from lung, heart, and other tissues at post-mortem as well as nasal mucosa swabs from cases of BRD in Australian feedlots (2004-2019). Broth microdilution Minimal Inhibitory Concentration (MIC) assays were determined for 19 antimicrobials using three different media (CLSI approved Veterinary Fastidious Medium [VFM], Mueller-Hinton fastidious broth medium supplemented with yeast extract [MHF-Y] and Columbia Broth [CB] supplemented with 5% lysed horse blood). For all antimicrobials, MICs obtained using CB medium were identical or within 1 dilution step of the MICs obtained for VFM and MHF-Y media. Therefore, CB may be a suitable medium for H. somni antimicrobial susceptibility testing similar to MHF-Y medium. None of the 70 Australian H. somni isolates exhibited resistance to antimicrobials with CLSI breakpoints including those commonly used in the treatment of BRD in Australia (first-line tetracyclines [chlortetracycline and oxytetracycline], second-line macrolides [tulathromycin], and third-line extended-spectrum cephalosporin [ceftiofur]). Whole-genome sequence analysis of 65 H. somni isolates for genomic single nucleotide polymorphism differences identified four phylogenetic clusters, each containing isolates from different Australian states, feedlots and tissue sources that clustered together. These findings demonstrate limited genetic diversity and the absence of significant antimicrobial resistance among Australian isolates of H. somni isolated from feedlot cattle.

Correction: Alhamami et al. First Emergence of Resistance to Macrolides and Tetracycline Identified in Mannheimia haemolytica and Pasteurella multocida Isolates from Beef Feedlots in Australia. Microorganisms 2021, 9, 1322.

The authors wish to make the following corrections to this paper [...].

Complete Genome Sequence of Pasteurella multocida Sequence Type 394, Isolated from a Case of Bovine Respiratory Disease in Australia.

Here, we present the completely closed genome sequence of Pasteurella multocida 17BRD-035, a bovine respiratory disease (BRD) pathogen from Queensland, Australia, with genes that confer resistance to ß-lactams, tilmicosin, and tetracycline. It consists of a single 2,624,884-bp chromosome and an average GC content of 40.23% and belongs to the newly described Rural Industries Research and Development Corporation (RIRDC) sequence type 394.

Impact of a Novel Anticoccidial Analogue on Systemic Staphylococcus aureus Infection in a Bioluminescent Mouse Model.

In this study, we investigated the potential of an analogue of robenidine (NCL179) to expand its chemical diversity for the treatment of multidrug-resistant (MDR) bacterial infections. We show that NCL179 exhibits potent bactericidal activity, returning minimum inhibitory concentration/minimum bactericidal concentrations (MICs/MBCs) of 1-2 µg/mL against methicillin-resistant Staphylococcus aureus, MICs/MBCs of 1-2 µg/mL against methicillin-resistant S. pseudintermedius and MICs/MBCs of 2-4 µg/mL against vancomycin-resistant enterococci. NCL179 showed synergistic activity against clinical isolates and reference strains of Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa in the presence of sub-inhibitory concentrations of colistin, whereas NCL179 alone had no activity. Mice given oral NCL179 at 10 mg/kg and 50 mg/kg (4 × doses, 4 h apart) showed no adverse clinical effects and no observable histological effects in any of the organs examined. In a bioluminescent S. aureus sepsis challenge model, mice that received four oral doses of NCL179 at 50 mg/kg at 4 h intervals exhibited significantly reduced bacterial loads, longer survival times and higher overall survival rates than the vehicle-only treated mice. These results support NCL179 as a valid candidate for further development to treat MDR bacterial infections as a stand-alone antibiotic or in combination with existing antibiotic classes.