c Acinetobacter baumannii, a Gram-negative multidrug-resistant (MDR) bacterium, is now recognized as one of the more common nosocomial pathogens. Because most clinical isolates are found to be multidrug resistant, alternative therapies need to be developed to control this pathogen. We constructed a bacteriophage genomic library based on prophages induced from 13 A. baumannii strains and screened it for genes encoding bacteriolytic activity. Using this approach, we identified 21 distinct lysins with different activities and sequence diversity that were capable of killing A. baumannii. The lysin (PlyF307) displaying the greatest activity was further characterized and was shown to efficiently kill (>5-log-unit decrease) all tested A. baumannii clinical isolates. Treatment with PlyF307 was able to significantly reduce planktonic and biofilm A. baumannii both in vitro and in vivo. Finally, PlyF307 rescued mice from lethal A. baumannii bacteremia and as such represents the first highly active therapeutic lysin specific for Gram-negative organisms in an array of native lysins found in Acinetobacter phage. Members of Acinetobacter are soil bacteria that frequently colonize the human skin without harm (1). However, in environments in which individuals are immunocompromised or suffer from a variety of wounds (e.g., in hospital settings or on battlefields), Acinetobacter baumannii can cause severe life-threatening infections (2-4). Symptoms of A. baumannii infections range from mild skin wounds and urinary tract infections to more severe conditions, including pneumonia, meningitis, and sepsis (5). A. baumannii is now one of the most common causes of hospital-acquired pneumonia (2) and sepsis; while not common (only 1.3% of all sepsis cases), it is associated with mortality rates of up to 58% (6).One of the main threats from A. baumannii is the high rate of resistance to antibiotics commonly used to treat Gram-negative infections. More than 80% of Acinetobacter species are considered to be multidrug resistant (MDR) (i.e., resistant to at least three classes of antibiotics), resulting in infections with poor clinical outcomes, including high rates of morbidity and death, prolonged hospital stays, and substantial health care expenses (3, 7). In addition, several strains of pan-drug-resistant A. baumannii have been isolated, showing resistance to a wide variety of clinically used antibiotics (8). A. baumannii is also capable of surviving treatments with detergents and disinfectants, dehydration, and UV radiation and thus is difficult to eradicate from surfaces in hospital environments (9, 10). The organism not only is intrinsically resistant to many antibiotics (owing to -lactamases, weak membrane permeability, and efficient efflux systems) but also can readily acquire foreign plasmids and is considered to have a high degree of genetic plasticity (11). Outbreaks caused by MDR Acinetobacter have been reported from hospitals worldwide; more recently, they have become a serious problem in military medical facilities (4). One of ...
Acinetobacter baumannii is a Gram-negative bacterial pathogen responsible for a range of nosocomial infections. The recent rise and spread of multidrug-resistant A. baumannii clones has fueled a search for alternative therapies, including bacteriophage endolysins with potent antibacterial activities. A common feature of these lysins is the presence of a highly positively charged C-terminal domain with a likely role in promoting outer membrane penetration. In the present study, we show that the C-terminal amino acids 108 to 138 of phage lysin PlyF307, named P307, alone were sufficient to kill A. baumannii (>3 logs). Furthermore, P307 could be engineered for improved activity, the most active derivative being P307 SQ-8C (>5-log kill). Both P307 and P307 SQ-8C showed high in vitro activity against A. baumannii in biofilms. Moreover, P307 SQ-8C exhibited MICs comparable to those of levofloxacin and ceftazidime and acted synergistically with polymyxin B. Although the peptides were shown to kill by disrupting the bacterial cytoplasmic membrane, they did not lyse human red blood cells or B cells; however, serum was found to be inhibitory to lytic activity. In a murine model of A. baumannii skin infection, P307 SQ-8C reduced the bacterial burden by ϳ2 logs in 2 h. This study demonstrates the prospect of using peptide derivatives from bacteriophage lysins to treat topical infections and remove biofilms caused by Gram-negative pathogens.
Streptococcus suis infects pigs worldwide and may be zoonotically transmitted to humans with a mortality rate of up to 20%. S. suis has been shown to develop in vitro resistance to the two leading drugs of choice, penicillin and gentamicin. Because of this, we have pursued an alternative therapy to treat these pathogens using bacteriophage lysins. The bacteriophage lysin PlySs2 is derived from an S. suis phage and displays potent lytic activity against most strains of that species including serotypes 2 and 9. At 64 μg/ml, PlySs2 reduced multiple serotypes of S. suis by 5 to 6-logs within 1 hour in vitro and exhibited a minimum inhibitory concentration (MIC) of 32 μg/ml for a S. suis serotype 2 strain and 64 μg/ml for a serotype 9 strain. Using a single 0.1-mg dose, the colonizing S. suis serotype 9 strain was reduced from the murine intranasal mucosa by >4 logs; a 0.1-mg dose of gentamicin reduced S. suis by <3-logs. A combination of 0.05 mg PlySs2 + 0.05 mg gentamicin reduced S. suis by >5-logs. While resistance to gentamicin was induced after systematically increasing levels of gentamicin in an S. suis culture, the same protocol resulted in no observable resistance to PlySs2. Thus, PlySs2 has both broad and high killing activity against multiple serotypes and strains of S. suis, making it a possible tool in the control and prevention of S. suis infections in pigs and humans.
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