Man-Hua Zhu

Bio: Man-Hua Zhu is an academic researcher from Zhejiang University. The author has contributed to research in topics: Tigecycline & Acinetobacter baumannii. The author has an hindex of 3, co-authored 4 publications receiving 162 citations.

Molecular Epidemiology and Mechanisms of Tigecycline Resistance in Clinical Isolates of Acinetobacter baumannii from a Chinese University Hospital

Abstract: For its remarkable ability to acquire antibiotic resistance and to survive in nosocomial environments, Acinetobacter baumannii has become a significant nosocomial infectious agent worldwide. Tigecycline is one of the few therapeutic options to treat infections caused by A. baumannii isolates. However, tigecycline resistance has been increasingly reported. Our aim was to assess the prevalence and characteristics of efflux-based tigecycline resistance in clinical isolates of A. baumannii collected from a hospital in China. A total of 74 A. baumannii isolates including 64 tigecycline non-susceptible A. baumannii (TNAB) and 10 tigecycline susceptible A. baumannii (TSAB) isolates were analyzed. The majority of them were detected to be positive for adeABC , adeRS , adeIJK and abeM, while the adeE gene was found in only one TSAB isolate. Compared with TSAB isolates, the mean expression level of adeB , adeJ, adeG and abeM in TNAB isolates were observed to increase by 29-, 3-, 0.7- and 1-fold, respectively. The efflux pump inhibitors (EPIs) PAβN and carbonyl cyanide 3-chlorophenylhydrazone (CCCP) could partially reverse the resistance pattern of tigecycline. Moreover, tetX1 gene was detected in 12 (18.8%) TNAB isolates. To our knowledge, this is the first report that tetX1 gene was detected in the A. baumannii isolates. ST208 and ST191 which both clustered into clonal complex 92 (CC92) were the predominant sequence types (STs). This study showed that active efflux pump AdeABC appeared to play important roles in the tigecycline resistance of A. baumannii. The dissemination of TNAB isolates in our hospital is mainly attributable to the spread of CC92.

blaKPC and rmtB on a single plasmid in Enterobacter amnigenus and Klebsiella pneumoniae isolates from the same patient

Abstract: Enterobacter amnigenus (EA76) and Klebsiella pneumoniae (KP76) isolates with multidrug-resistant (MDR) patterns were identified from the same patient in the neurosurgery department of our hospital. An outbreak of MDR K. pneumoniae had also occurred in this department. To characterize the resistance mechanism and molecular epidemiology of these isolates, sequential experiments including antimicrobial susceptibility testing, polymerase chain reaction (PCR), plasmid analysis, pulsed field gel electrophoresis (PFGE), and multilocus sequence typing (MLST) were performed. EA76 and KP76 were resistant to all of the antibiotics tested, except colistin and tigecycline. blaKPC-2, blaTEM-1, blaSHV-12, blaCTX-M-3, blaCTX-M-14, and rmtB genes were identified in both isolates, with blaKPC-2, blaTEM-1, blaCTX-M-14, and rmtB being co-carried on one plasmid in each isolate. Further analysis showed different restriction patterns between the two KPC-carrying plasmids. Of the 11 carbapenem-resistant isolates found in the outbreak, all were resistant to all of the β-lactams tested, with 63.64% (7/11) also exhibiting resistance to aminoglycosides and 72.73% (8/11) exhibiting resistance to quinolones. PCR analysis and molecular typing of the 11 K. pneumoniae strains revealed that the seven aminoglycoside-resistant isolates shared the same antibiotic-resistant gene pattern and identical or one-band-difference PFGE profiles relative to KP76. In addition, all of the eight aminoglycoside-resistant isolates, including KP76, belonged to the national epidemic clone ST11. The overall results indicate the emergence of E. amnigenus and outbreak of ST11 K. pneumoniae, with both co-harboring blaKPC and rmtB genes on a single plasmid in our neurosurgery wards.

Novel action of 3,4‐DAA ameliorating acute liver allograft injury

Abstract: The anti-allergic drug, N-(3,4-dimethoxycinnamonyl) anthranilic acid (3,4-DAA), is a synthetic anthranilic acid derivative that has been used therapeutically in Japan for many years. In this study, to investigate the effects of 3,4-DAA in allograft immunorejection model, liver orthotopic transplants were performed using inbred male Dark Agouti donors and Lewis rat recipients (allografts). The levels of indoleamine 2,3-dioxygenases (IDO) enzymic activities in five groups, allografts (control), dimethyl sulphoxide-treated group (vehicle control), 200 mg·kg–1·day–1 of 3,4-DAA-treated group and 200 mg·kg–1·day–1 of 3,4-DAA + 5 mg·ml–1 of 1-methyl-D-tryptophan (1-MT)-treated group were confirmed by determination of L-kynurenine (L-Kyn) concentrations. The serum alanine aminotransferase levels in 3,4-DAA-treated rats significantly decreased compared with those in mock and control group, whereas treatment of 1-MT in allografts led to the opposite effect. Administration of 3,4-DAA reduced histological severity of allograft immunorejection, decreased serum levels of cytokines tumour necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), and raised serum levels of interleukin-10 (IL-10), suggesting that 3,4-DAA has both anti-inflammatory and anti-immunorejection properties through IDO in immune regulation and may therefore be useful in filling an unmet need, in the treatment of allograft immunorejection. Copyright © 2011 John Wiley & Sons, Ltd.

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

Abstract: The global emergence of multidrug-resistant Gram-negative bacteria is a growing threat to antibiotic therapy. The chromosomally encoded drug efflux mechanisms that are ubiquitous in these bacteria greatly contribute to antibiotic resistance and present a major challenge for antibiotic development. Multidrug pumps, particularly those represented by the clinically relevant AcrAB-TolC and Mex pumps of the resistance-nodulation-division (RND) superfamily, not only mediate intrinsic and acquired multidrug resistance (MDR) but also are involved in other functions, including the bacterial stress response and pathogenicity. Additionally, efflux pumps interact synergistically with other resistance mechanisms (e.g., with the outer membrane permeability barrier) to increase resistance levels. Since the discovery of RND pumps in the early 1990s, remarkable scientific and technological advances have allowed for an in-depth understanding of the structural and biochemical basis, substrate profiles, molecular regulation, and inhibition of MDR pumps. However, the development of clinically useful efflux pump inhibitors and/or new antibiotics that can bypass pump effects continues to be a challenge. Plasmid-borne efflux pump genes (including those for RND pumps) have increasingly been identified. This article highlights the recent progress obtained for organisms of clinical significance, together with methodological considerations for the characterization of MDR pumps.

Biology of Acinetobacter baumannii: Pathogenesis, Antibiotic Resistance Mechanisms, and Prospective Treatment Options.

Abstract: Acinetobacter baumannii is undoubtedly one of the most successful pathogens responsible for hospital-acquired nosocomial infections in the modern healthcare system. Due to the prevalence of infections and outbreaks caused by multi-drug resistant A. baumannii, few antibiotics are effective for treating infections caused by this pathogen. To overcome this problem, knowledge of the pathogenesis and antibiotic resistance mechanisms of A. baumannii is important. In this review, we summarize current studies on the virulence factors that contribute to A. baumannii pathogenesis, including porins, capsular polysaccharides, lipopolysaccharides, phospholipases, outer membrane vesicles, metal acquisition systems, and protein secretion systems. Mechanisms of antibiotic resistance of this organism, including acquirement of -lactamases, up-regulation of multidrug efflux pumps, modification of aminoglycosides, permeability defects, and alteration of target sites, are also discussed. Lastly, novel prospective treatment options for infections caused by multi-drug resistant A. baumannii are summarized.

Infection and Drug Resistance

Abstract: Dr Benjamin A H Jensen Dr Aarabi Dr Mera A Ababneh Dr Albert Abaka-Yawson Dr Mohamed Salah Abassi Dr Getahun Abate Dr Tarek Mohamed Abd ElAziz Dr Rehab M Abd El-Baky Dr Amir Abdoli Dr Akebe Luther King Abia Dr Fatma Ben Abid Prof Dr Khaled M Aboshanab Mr Ashenafi Abossie Dr Abouelfetouh Dr Maja Abram Dr Sawsan Abuhammad Dr Abulebda Professor Ali Acar Mr Oliver Okoth Achila Dr Stefan Acosta Dr Azeez Adeboye Dr Sanjib Adhikari Prof Dr Muhammad Sohail Afzal Dr Fabio Aguiar-Alves Dr Thomas Agyarko-Poku Dr Irfan Ahmad Dr Suhail Ahmad Dr Hafiz Ahmad Dr Elham Ahmadi Dr Zahra Ahmadinejad Dr Ehsan Ahmadpour Dr Haroon Ahmed Dr Firoz Ahmed Dr Wan M Aizat Dr Abraham Ajayi Dr Ali Akbar Dr Sami Akbulut Dr Hashaam Akhtar Professor Ala-Eddin Al Moustafa Dr Al-Hasan Dr Ali Al-Jumaili Dr Alexandre Alanio Dr Eliana Alcaraz Dr Maria D Alcantar Curiel Dr Gaetano Alfano Prof Dr Abdelazeem Algammal Dr Iftikhar Ali Dr Musa Mohammed Ali Dr Ihsan Ali Dr Mohammad Javed Ali Dr Ali Muhsin Ali Dr Shahzad Ali Dr Sheikh Alif Professor Michael Alifrangis Dr Reem Aljindan Prof Dr Karel Allegaert Dr Rosalie Allison Dr Ammar Almaaytah Dr Dhary Alewy Almashhadany Dr Tarig Alnour Dr Bandar Alosaimi Mr Abdullah Alqarihi Dr Alian A Alrasheedy Dr Eduardo Amaral Dr Gul Ambreen Professor Gobena Ameni Dr Ahmed Ammar Dr Linda Amoah Professor Luca Ampollini Dr Edina Amponsah-Dacosta Dr Mirko Ancillotti Ms Motswedi Anderson Dr Angel Andrade Dr Sergio Angel Dr Angkasekwinai Dr Archana Angrup Dr Enoch Aninagyei Dr Shamshul Ansari Dr Beena Antony Dr Nopporn Apiwattanakul Dr Amjad Islam Aqib Professor Mohammad Arabestani Dr Sheila Araujo Teles Dr Balew Arega Dr Gunjan Arora Dr Muhammad Imran Arshad Dr Yasir Arshad Dr Kovy Arteaga-Livias Dr Mohd Hafiz Arzmi Dr Mohammad Reza Asadi Karam Dr Takanori Asakura Dr Prince Asare Dr Mohammad Asgharzadeh Dr Hossam Ashour Dr Abdullah Tarik Aslan Dr Alaa Atamna Dr Nur Atik Dr Meiji Soe Aung Dr Wah Wah Aung Professor Sergey Avdeev Dr Akshay Avula Dr Babafela Awosile Dr Gajendra Kumar Azad Dr Davood Azadi Mr Zelalem Nigussie Azene Dr Afzal Azim Mr Muhammad Majid Aziz Dr Martin Sima Dr Azer Ozad Duzgun Dr Kenan Cetin Dr Aysegul Copur Cicek Dr Ines Bado Dr Fang Bai Dr J Kevin Baird Dr Andrea Ballini Prof Dr Zulqarnain Baloch Dr Joseph Baruch Baluku Dr Banaei Prof Dr Tuhina Banerjee Dr Tuhina Banerjee Mr Agegnehu Bante Dr Humberto Barrios Camacho Dr Mazin Barry Dr Bruno Barsic Dr Christopher S von Bartheld Dr Dariusz Bartosik Dr Joseph Baruch Baluku Dr Rasha Barwa Dr Saurav Basu Dr George Bayliss

Next-generation approaches to understand and combat the antibiotic resistome

Abstract: Antibiotic resistance is a natural feature of diverse microbial ecosystems. Although recent studies of the antibiotic resistome have highlighted barriers to the horizontal transfer of antibiotic resistance genes between habitats, the rapid global spread of genes that confer resistance to carbapenem, colistin and quinolone antibiotics illustrates the dire clinical and societal consequences of such events. Over time, the study of antibiotic resistance has grown from focusing on single pathogenic organisms in axenic culture to studying antibiotic resistance in pathogenic, commensal and environmental bacteria at the level of microbial communities. As the study of antibiotic resistance advances, it is important to incorporate this comprehensive approach to better inform global antibiotic resistance surveillance and antibiotic development. It is increasingly becoming apparent that although not all resistance genes are likely to geographically and phylogenetically disseminate, the threat presented by those that are is serious and warrants an interdisciplinary research focus. In this Review, we highlight seminal work in the resistome field, discuss recent advances in the studies of resistomes, and propose a resistome paradigm that can pave the way for the improved proactive identification and mitigation of emerging antibiotic resistance threats.

Emergence of plasmid-mediated high-level tigecycline resistance genes in animals and humans

Abstract: Tigecycline is a last-resort antibiotic that is used to treat severe infections caused by extensively drug-resistant bacteria. tet(X) has been shown to encode a flavin-dependent monooxygenase that modifies tigecycline1,2. Here, we report two unique mobile tigecycline-resistance genes, tet(X3) and tet(X4), in numerous Enterobacteriaceae and Acinetobacter that were isolated from animals, meat for consumption and humans. Tet(X3) and Tet(X4) inactivate all tetracyclines, including tigecycline and the newly FDA-approved eravacycline and omadacycline. Both tet(X3) and tet(X4) increase (by 64-128-fold) the tigecycline minimal inhibitory concentration values for Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii. In addition, both Tet(X3) (A. baumannii) and Tet(X4) (E. coli) significantly compromise tigecycline in in vivo infection models. Both tet(X3) and tet(X4) are adjacent to insertion sequence ISVsa3 on their respective conjugative plasmids and confer a mild fitness cost (relative fitness of >0.704). Database mining and retrospective screening analyses confirm that tet(X3) and tet(X4) are globally present in clinical bacteria-even in the same bacteria as blaNDM-1, resulting in resistance to both tigecycline and carbapenems. Our findings suggest that both the surveillance of tet(X) variants in clinical and animal sectors and the use of tetracyclines in food production require urgent global attention.