Antifolates targeting folate biosynthesis within the shikimate-chorismate-folate metabolic pathway are ideal and selective antimicrobials, since higher eukaryotes lack this pathway and rely on an exogenous source of folate. Resistance to the available antifolates, inhibiting the folate pathway, underlines the need for novel antibiotic scaffolds and molecular targets. While para-aminobenzoic acid synthesis within the chorismate pathway constitutes a novel molecular target for antifolates, abyssomicins are its first known natural inhibitors. This review describes the abyssomicin family, a novel spirotetronate polyketide Class I antimicrobial. It summarizes synthetic and biological studies, structural, biosynthetic, and biological properties of the abyssomicin family members. This paper aims to explain their molecular target, mechanism of action, structure–activity relationship, and to explore their biological and pharmacological potential. Thirty-two natural abyssomicins and numerous synthetic analogues have been reported. The biological activity of abyssomicins includes their antimicrobial activity against Gram-positive bacteria and mycobacteria, antitumor properties, latent human immunodeficiency virus (HIV) reactivator, anti-HIV and HIV replication inducer properties. Their antimalarial properties have not been explored yet. Future analoging programs using the structure–activity relationship data and synthetic approaches may provide a novel abyssomicin structure that is active and devoid of cytotoxicity. Abyssomicin J and atrop-o-benzyl-desmethylabyssomicin C constitute promising candidates for such programs.

Antimicrobial susceptibility testing is an essential tool to the veterinarian for selecting the most appropriate agent for treatment of bacterial diseases of animals. The availability of well-defined methods that incorporate the necessary quality controls coupled to clinical outcome data is foundational in providing relevant test results for clinical decisions. Since 1993, the Clinical Laboratory and Standards Institute (CLSI) Subcommittee on Veterinary Antimicrobial Susceptibility Testing (VAST) has developed specific test methods and interpretive criteria for veterinary pathogens. This information has allowed for veterinarians to more effectively treat animal diseases thereby protecting both animal welfare and human food security. Moreover, the availability of standardized test methods for veterinary pathogens has allowed for the development of antimicrobial surveillance programs to detect the emergence of resistance among veterinary pathogens. Future work by the VAST and other groups will be critical to expanding the current test methods and interpretive criteria to more pathogen-antibacterial combinations, as well as, the incorporation of genomic information for routine antimicrobial susceptibility testing in the veterinary diagnostic laboratory.

Antimicrobial peptides (AMPs) hold promise as the next generation of antimicrobial agents, but often suffer from rapid degradation in vivo. Modifying AMPs with non-proteinogenic residues such as peptoids (oligomers of N-alkylglycines) provides the potential to improve stability. We have identified two novel peptoid-based compounds, B1 and D2, which are effective against the canine skin pathogen Staphylococcus pseudintermedius, the main cause of antibiotic use in companion animals. We report on their potential to treat infections topically by characterizing their release from formulation and in vitro ADME properties. In vitro ADME assays included skin penetration profiles, stability to proteases and liver microsomes, and plasma protein binding. Both B1 and D2 were resistant to proteases and >98% bound to plasma proteins. While half-lives in liver microsomes for both were >2 h, peptoid D2 showed higher stability to plasma proteases than the peptide-peptoid hybrid B1 (>2 versus 0.5 h). Both compounds were suitable for administration in an oil-in-water cream formulation (50% release in 8 h), and displayed no skin permeation, in the absence or presence of skin permeability modifiers. Our results indicate that these peptoid-based drugs may be suitable as antimicrobials for local treatment of canine superficial pyoderma and that they can overcome the inherent limitations of stability encountered in peptides.

Clinafloxacin is a broad-spectrum fluoroquinolone that was originally developed and subsequently abandoned in the late 1990s as a human health antibiotic for respiratory diseases. The purpose of this study was to investigate the activity of clinafloxacin as a possible treatment for respiratory disease in cattle and pigs. Minimum inhibitory concentration (MIC) values were determined using Clinical and Laboratory Standards Institute recommended procedures with recent strains from the Zoetis culture collection. Rodent efficacy was determined in CD-1 mice infected systemically or intranasally with bovine Mannheimia haemolytica or Pasteurella multocida, or swine Actinobacillus pleuropneumoniae, and administered clinafloxacin for determination of ED₅₀ (efficacious dose-50%) values. The MIC₉₀ values for clinafloxacin against bovine P. multocida, M. haemolytica, Histophilus somni, and M. bovis were 0.125, 0.5, 0.125, and 1 μg/ml, respectively, and the MIC₉₀ values against swine P. multocida, A. pleuropneumoniae, S. suis, and M. hyopneumoniae were ≤0.03, ≤0.03, 0.125, and ≤0.008 μg/ml, respectively. Efficacy in mouse models showed average ED₅₀ values of 0.019 mg/kg/dose in the bovine M. haemolytica systemic infection model, 0.55 mg/kg in the bovine P. multocida intranasal lung challenge model, 0.08 mg/kg/dose in the bovine P. multocida systemic infection model, and 0.7 mg/kg/dose in the swine A. pleuropneumoniae systemic infection model. Clinafloxacin shows good in vitro activity and efficacy in mouse models and may be a novel treatment alternative for the treatment of respiratory disease in cattle and pigs.

Antimicrobial susceptibility test results for trimethoprim-sulfadiazine withStreptococcus equisubspecies are interpreted based on human data for trimethoprim-sulfamethoxazole. The veterinary-specific data generated in this study support a single breakpoint for testing trimethoprim-sulfamethoxazole and/or trimethoprim-sulfadiazine withS. equi. This study indicates trimethoprim-sulfamethoxazole as an acceptable surrogate for trimethoprim-sulfadiazine withS. equi.