In vitro activity of XF-73, a novel antibacterial agent, against antibiotic-sensitive and -resistant Gram-positive and Gram-negative bacterial species

Abstract

The antibacterial activity of XF-73, a dicationic porphyrin drug, was investigated against a range of Gram-positive and Gram-negative bacteria with known antibiotic resistance profiles, including resistance to cell wall synthesis, protein synthesis, and DNA and RNA synthesis inhibitors as well as cell membrane-active antibiotics. Antibiotic-sensitive strains for each of the bacterial species tested were also included for comparison purposes. XF-73 was active [minimum inhibitory concentration (MIC) 0.25-4 mg/L] against all of the Gram-positive bacteria tested, irrespective of the antibiotic resistance profile of the isolates, suggesting that the mechanism of action of XF-73 is unique compared with the major antibiotic classes. Gram-negative activity was lower (MIC 1 mg/L to > 64 mg/L). Minimum bactericidal concentration data confirmed that the activity of XF-73 was bactericidal. Time-kill kinetics against healthcare-associated and community-associated meticillin-resistant Staphylococcus aureus isolates demonstrated that XF-73 was rapidly bactericidal, with > 5 log(10) kill obtained after 15 min at 2 x MIC, the earliest time point sampled. The post-antibiotic effect (PAE) for XF-73 under conditions where the PAE for vancomycin was < 0.4h was found to be > 5.4 h. XF-73 represents a novel broad-spectrum Gram-positive antibacterial drug with potentially beneficial characteristics for the treatment and prevention of Gram-positive bacterial infections.

Antibiotics in the clinical pipeline at the end of 2015

“…165 Exeporfinium chloride (27) is a photosensitizer that has broad-spectrum G+ve activity [166][167][168][169][170] and activity against Candida albicans. 171 Auriclosene (28) (NVC-422, N,N-dichloro-2,2-dimethyltaurine) is an N-dichlorotaurine analog being evaluated in phase-II trials by NovaBay Pharmaceuticals, Inc. (Emeryville, CA, USA) as an irrigation solution on urinary catheter patency (NCT02130518).…”

Mechanism of Action of a Membrane-Active Quinoline-Based Antimicrobial on Natural and Model Bacterial Membranes

“…Although the protein synthesis inhibitor mupirocin is currently widely used for anti-MRSA nasal decolonisation, it is not active against non-multiplying persister bacteria which constitute a reservoir for recolonisation [5] . In addition to this, an increased prevalence of mupirocin resistant MRSA [6] has led to the development of more effective alternatives, including the experimental antimicrobials LTX-109 [7] and XF-73 [8] in addition to HT61 [1] .The mode of action of HT61 has not hitherto been thoroughly investigated, however initial cell-based assays showed that HT61 is capable of depolarising the cytoplasmic membrane ofGram positives with further evidence from electron microscopy suggesting that HT61 causes lysis of either the membrane or cell wall [1,4] . The putative membrane-targeting of HT61 may provide some explanation for its potency against non-multiplying MRSA [9] , and suggests that its mechanism of action may be similar to those of other membrane-active antibiotics such as daptomycin [10] , cationic antibiotics such as polymyxins B and E (colistin), gramicidin S [11] and cationic antimicrobials, for example chlorhexidine [12] and ceragenins [13] .…”

“…Although the protein synthesis inhibitor mupirocin is currently widely used for anti-MRSA nasal decolonisation, it is not active against non-multiplying persister bacteria which constitute a reservoir for recolonisation [5] . In addition to this, an increased prevalence of mupirocin resistant MRSA [6] has led to the development of more effective alternatives, including the experimental antimicrobials LTX-109 [7] and XF-73 [8] in addition to HT61 [1] .…”

Investigation of the Potential for Mutational Resistance to XF-73, Retapamulin, Mupirocin, Fusidic Acid, Daptomycin, and Vancomycin in Methicillin-Resistant Staphylococcus aureus Isolates during a 55-Passage Study

“…1), and previous studies have shown that XF-73 has potent Gram-positive in vitro bactericidal activity against a range of clinically important S. aureus isolates, including methicillin-sensitive S. aureus (MSSA), health care-associated MRSA (HA-MRSA), and CA-MRSA (minimal bactericidal concentration at which 90% of strains tested are killed [MBC 90 ], 0.5 g/ml) (10). XF-73 has rapid activity, with a Ͼ4-log reduction in CFU obtained after 5 min incubation in growth medium (27).…”