Hypoxia inducible factor-1 (HIF-1) is a transcription factor that is a major regulator of energy homeostasis and cellular adaptation to low oxygen stress. HIF-1 is also activated in response to bacterial pathogens and supports the innate immune response of both phagocytes and keratinocytes. In this work, we show that a new pharmacological compound AKB-4924 (Akebia Therapeutics) increases HIF-1α levels and enhances the antibacterial activity of phagocytes and keratinocytes against both methicillin-sensitive and -resistant strains of Staphylococcus aureus in vitro. AKB-4924 is also effective in stimulating the killing capacity of keratinocytes against the important opportunistic skin pathogens Pseudomonas aeruginosa and Acinitobacter baumanii. The effect of AKB-4924 is mediated through the activity of host cells, as the compound exerts no direct antimicrobial activity. Administered locally as a single agent, AKB-4924 limits S. aureus proliferation and lesion formation in a mouse skin abscess model. This approach to pharmacologically boost the innate immune response via HIF-1 stabilization may serve as a useful adjunctive treatment for antibiotic-resistant bacterial infections.

Based on in vitro synergy studies, the addition of nafcillin to daptomycin was used to treat refractory methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Daptomycin is a de facto cationic antimicrobial peptide in vivo, with antistaphylococcal mechanisms reminiscent of innate host defense peptides (HDPs). In this study, the effects of nafcillin on HDP activity against MRSA were examined in vitro and in vivo. Exposures to β-lactam antimicrobials in general, and nafcillin in particular, significantly increased killing of S. aureus by selected HDPs from, keratinocytes, neutrophils and platelets. This finding correlated with enhanced killing of MRSA by whole blood, neutrophils and keratinocytes after growth in nafcillin. Finally, nafcillin pretreatment ex vivo reduced MRSA virulence in a murine subcutaneous infection model. Despite the lack of direct activity against MRSA, these studies show potent, consistent, and generalized nafcillin-mediated ‘sensitization’ to increased killing of MRSA by various components of the innate host response. The use of nafcillin as adjunctive therapy in MRSA bacteremia merits further study and should be considered in cases refractory to standard therapy.

Coxsackieviruses (CVs) are relatively common viruses associated with a number of serious human diseases, including myocarditis and meningo-encephalitis. These viruses are considered cytolytic yet can persist for extended periods of time within certain host tissues requiring evasion from the host immune response and a greatly reduced rate of replication. A member of Picornaviridae family, CVs have been historically considered non-enveloped viruses – although recent evidence suggest that CV and other picornaviruses hijack host membranes and acquire an envelope. Acquisition of an envelope might provide distinct benefits to CV virions, such as resistance to neutralizing antibodies and efficient nonlytic viral spread. CV exhibits a unique tropism for progenitor cells in the host which may help to explain the susceptibility of the young host to infection and the establishment of chronic disease in adults. CVs have also been shown to exploit autophagy to maximize viral replication and assist in unconventional release from target cells. In this article, we review recent progress in clarifying virus replication and dissemination within the host cell, identifying determinants of tropism, and defining strategies utilized by the virus to evade the host immune response. Also, we will highlight unanswered questions and provide future perspectives regarding the potential mechanisms of CV pathogenesis.

The rapid rise in antimicrobial resistance in bacteria has generated an increased demand for the development of novel therapies to treat contemporary infections, especially those caused by methicillin-resistant Staphylococcus aureus (MRSA). However, antimicrobial development has been largely abandoned by the pharmaceutical industry. We recently isolated the previously described thiopeptide antibiotic nosiheptide from a marine actinomycete strain and evaluated its activity against contemporary clinically relevant bacterial pathogens. Nosiheptide exhibited extremely potent activity against all contemporary MRSA strains tested including multiple drug-resistant clinical isolates, with MIC values ≤ 0.25 mg/L. Nosiheptide was also highly active against Enterococcus spp and the contemporary hypervirulent BI strain of Clostridium difficile but was inactive against most Gram-negative strains tested. Time-kill analysis revealed nosiheptide to be rapidly bactericidal against MRSA in a concentration- and time-dependent manner, with a nearly 2-log kill noted at 6 hours at 10X MIC. Furthermore, nosiheptide was found to be non-cytotoxic against mammalian cells at >> 100X MIC, and its anti-MRSA activity was not inhibited by 20% human serum. Notably, nosiheptide exhibited a significantly prolonged post-antibiotic effect (PAE) against both healthcare- and community-associated MRSA compared to vancomycin. Nosiheptide also demonstrated in vivo activity in a murine model of MRSA infection, and therefore represents a promising antibiotic for the treatment of serious infections caused by contemporary strains of MRSA.

The emergence of virulent, drug-resistant bacterial strains coupled with a minimal output of new pharmaceutical agents to combat them makes this a critical time for antibacterial research. Aminoglycosides are a well-studied, highly potent class of naturally occurring antibiotics with scaffolds amenable to modification, and therefore, they provide an excellent starting point for the development of semisynthetic, next-generation compounds. To explore the potential of this approach, we synthesized a small library of aminoglycoside derivatives selectively and minimally modified at one or two positions with a guanidine group replacing the corresponding amine or hydroxy functionality. Most guanidino-aminoglycosides showed increased affinity for the ribosomal decoding rRNA site, the cognate biological target of the natural products, when compared with their parent antibiotics, as measured by an in vitro fluorescence resonance energy transfer (FRET) A-site binding assay. Additionally, certain analogues showed improved minimum inhibitory concentration (MIC) values against resistant bacterial strains, including methicillin-resistant Staphylococcus aureus (MRSA). An amikacin derivative holds particular promise with activity greater than or equal to the parent antibiotic in the majority of bacterial strains tested.

Anthracimycin is a recently discovered novel marine-derived compound with activity against Bacillus anthracis. We tested anthracimycin against an expanded panel of Staphylococcus aureus strains in vitro and in vivo. All strains of S. aureus tested, including methicillin-sensitive (MSSA), methicillin-resistant (MRSA), and vancomycin-resistant strains of S. aureus were sensitive to anthracimycin at minimum inhibitory concentrations (MIC) of < 0.25 mg/L. Although its post-antibiotic effects were minimal, anthracimycin exhibited potent and rapid bactericidal activity, with a > 4-log kill of USA300 MRSA within 3 hours at 5 times its MIC. At concentrations significantly below the MIC, anthracimycin slowed MRSA growth and potentiated the bactericidal activity of the human cathelicidin, LL-37. The bactericidal activity of anthracimycin was somewhat mitigated in the presence of 20% human serum, and the compound was minimally toxic to human cells, with an IC50 = 70 mg/L against human carcinoma cells. At concentrations near the MIC anthracimycin inhibited S. aureus nucleic acid synthesis as determined by optimized macromolecular synthesis methodology, with inhibition of DNA and RNA synthesis occurring in the absence of DNA intercalation. Anthracimycin at a single dose of 1 or 10 mg/kg was able to protect mice from MRSA-induced mortality in a murine peritonitis model of infection. Anthracimycin provides an interesting new scaffold for future development of a novel MRSA antibiotic.

The marine natural product, marinopyrrole A (1), was previously shown to have significant antibiotic activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Although compound (1) exhibits a significant reduction in MRSA activity in the presence of human serum, we have identified key modifications that partially restore activity. We previously reported our discovery of a chloro-derivative of marinopyrrole A (1a) featuring a 2–4 fold improved minimum inhibitory concentration (MIC) against MRSA, significantly less susceptibility to serum inhibition and rapid and concentration-dependent killing of MRSA. Here, we report a novel fluoro-derivative of marinopyrrole A (1e) showing an improved profile of potency, less susceptibility to serum inhibition, as well as rapid and concentration-dependent killing of MRSA.

Double whammy! Small molecules that inhibit Staphylococcus aureus dehydrosqualene synthase (CrtM) or host squalene synthase (SQS) are of interest as novel, innate immunity‐based therapeutics, blocking virulence or stimulating antibacterial neutrophil extracellular trap (NET) formation. The discovery of leads that do both represents a new route to treating staph infections.