MicrobiologyBytes

An unfailing observation over the past 70 years is that resistance to all antibiotics emerges eventually after use in the clinic. Where does this resistance come from? Recent work has shown that antibiotic resistance genes are common in metagenomes of ancient sediments. This prevalence of resistance, well before the use of antibiotics, denotes the importance of taking microbial chemical ecology and deep metagenomic profiling into account in the development and use of antibiotics.

Antibiotic resistance is ancient: implications for drug discovery. Trends Microbiol. 25 Jan 2012

Tweet

Humans have suffered from the burden of malarial infections for thousands of years, and the disease has greatly influenced human evolution and history. Malaria remains a devastating disease, and in developing countries within Africa, South America, and Asia, the size of its burden has stifled economic growth and development. Despite successful eradication campaigns in North America and Europe, global cases of the disease show little decline, and current improvements rely on pyrethroid treated bed nets and combination therapeutics containing artemisinin derivatives, both of which are susceptible to emerging resistance. Our ability to counter these vulnerabilities with new agents is hampered by the modest number of fully validated drug targets and our limited understanding of many aspects of parasite biology.

The Next Opportunity in Anti-Malaria Drug Discovery: The Liver Stage. (2011) PLoS Pathog 7(9): e1002178. doi:10.1371/journal.ppat.1002178
Malaria afflicts 350–500 million people annually, and this debilitating and deadly infectious disease exacts a heavy toll on susceptible populations around the globe. Efforts to find effective, safe, and low-cost drugs for malaria have sharply increased in recent years. Almost all of these efforts have focused on the cyclic blood stage of the disease, partly because the parasites can be easily maintained in culture through addition of human red blood cells to the growth medium, and partly because blood stage infection causes malaria’s characteristic symptoms. However, the asymptomatic liver stage, which the parasite goes through only once in its life history, presents the best opportunity for developing drugs that both hit new targets and also could be used in highly desirable eradication campaigns. Recent research, especially on the frequency of differentially expressed genes in blood and liver stage parasites, supports the feasibility of discovering stage-specific drugs. Discovering these drugs will require a high-throughput liver stage phenotypic screen comparable to the existing blood stage screens, and the basic tools for such a screen have recently been created.

Tweet

The emergence of resistance against most current drugs emphasizes the need to develop new approaches to control bacterial pathogens, particularly Staphylococcus aureus. Bacterial fatty acid synthesis is one such target that is being actively pursued by several research groups to develop anti-Staphylococcal agents. Recently, the wisdom of this approach has been challenged based on the ability of a Gram-positive bacterium to incorporate extracellular fatty acids and thus circumvent the inhibition of de novo fatty acid synthesis. The generality of this conclusion has been challenged, and there is enough diversity in the enzymes and regulation of fatty acid synthesis in bacteria to conclude that there is not a single organism that can be considered typical and representative of bacteria as a whole. We are left without a clear resolution to this ongoing debate and await new basic research to define the pathways for fatty acid uptake and that determine the biochemical and genetic mechanisms for the regulation of fatty acid synthesis in Gram-positive bacteria. These crucial experiments will determine whether diversity in the control of this important pathway accounts for the apparently different responses of Gram-positive bacteria to the inhibition of de novo fatty acid synthesis in presence of extracellular fatty acid supplements.

Is bacterial fatty acid synthesis a valid target for antibacterial drug discovery? Curr Opin Microbiol. Aug 20 2011

Tweet

Sudan is a large country with a diverse population and history of civil conflict. Poverty levels are high with a gross national income per capita of less than two thousand dollars. The country has a high burden of tuberculosis (TB) with an estimated 50,000 incident cases during 2009, when the estimated prevalence was 209 cases per 100,000 of the population. Few studies have been undertaken on TB in Sudan and the prevalence of drug resistant disease is not known.

In this study Mycobacterium tuberculosis isolates from 235 patients attending three treatment centers in Sudan were screened for susceptibility to isoniazid, rifampicin, ethambutol and streptomycin by the proportion method on Lowenstein Jensen media. 232 isolates were also genotyped by spoligotyping. Demographic details of patients were recorded using a structured questionnaire. Statistical analyses were conducted to examine the associations between drug resistance with risk ratios computed for a set of risk factors (gender, age, case status – new or relapse, geographic origin of the patient, spoligotype, number of people per room, marital status and type of housing).

Multi drug-resistant tuberculosis (MDR-TB), being resistance to at least rifampicin and isoniazid, was found in 5% of new cases and 24% of previously treated patients. Drug resistance was associated with previous treatment with risk ratios of 3.51 for resistance to any drug and 5.23 for MDR-TB. Resistance was also associated with the geographic region of origin of the patient, being most frequently observed in patients from the Northern region and least in the Eastern region with risk ratios of 7.43 and 14.09 for resistance to any drug and MDR-TB.

“We conclude that emergence of drug resistant tuberculosis has the potential to be a serious public health problem in Sudan and that strengthened tuberculosis control and improved monitoring of therapy is needed. Further surveillance is required to fully ascertain the extent of the problem.”

Tuberculosis in Sudan: a study of Mycobacterium tuberculosis strain genotype and susceptibility to anti-tuberculosis drugs. BMC Infectious Diseases 11:219 2011

Tweet

Combination antiretroviral therapy for HIV-1 infection has resulted in profound reductions in viremia and is associated with marked improvements in morbidity and mortality. Therapy is not curative, however, and prolonged therapy is complicated by drug toxicity and the emergence of drug resistance. Management of clinical drug resistance requires in depth evaluation, and includes extensive history, physical examination and laboratory studies. Appropriate use of resistance testing provides valuable information useful in constructing regimens for treatment-experienced individuals with viremia during therapy. This review outlines the emergence of drug resistance in vivo, and describes clinical evaluation and therapeutic options of the individual with rebound viremia during therapy.

Clinical Management of HIV Drug Resistance. Viruses 2011, 3(4), 347-378; doi:10.3390/v3040347

“We live in an era in which we depend on antibiotics, and other antimicrobial medicines to treat conditions that decades ago, or even a few years ago in the case of HIV/AIDS, would have proved fatal. When antimicrobial resistance – also known as drug resistance – occurs, it renders these medicines ineffective. For World Health Day 2011, WHO will be calling for intensified global commitment to safeguard these medicines for future generations. Antimicrobial resistance – the theme of World Health Day 2011, 7 April 2011 – and its global spread, threatens the continued effectiveness of many medicines used today to treat infectious diseases. For World Health Day 2011, WHO will call on governments and stakeholders to implement the policies and practices needed to prevent and counter the emergence of highly resistant microorganisms.”

via WHO | World Health Day – 7 April 2011

Cidofovir is an acyclic nucleoside analog approved since 1996 for clinical use in the treatment of cytomegalovirus (CMV) retinitis in AIDS patients. Cidofovir (CDV) has broad-spectrum activity against DNA viruses, including herpes-, adeno-, polyoma-, papilloma- and poxviruses. Among poxviruses, cidofovir has shown in vitro activity against orthopox [vaccinia, variola (smallpox), cowpox, monkeypox, camelpox, ectromelia], molluscipox [molluscum contagiosum] and parapox [orf] viruses. The anti-poxvirus activity of cidofovir in vivo has been shown in different models of infection when the compound was administered either intraperitoneal, intranasal (aerosolized) or topically. In humans, cidofovir has been successfully used for the treatment of recalcitrant molluscum contagiosum virus and orf virus in immunocompromised patients. CDV remains a reference compound against poxviruses and holds potential for the therapy and short-term prophylaxis of not only orthopox- but also parapox- and molluscipoxvirus infections.

Cidofovir Activity against Poxvirus Infections. (2010) Viruses 2(12): 2803-2830 doi:10.3390/v2122803

Related:

• Molluscum contagiosum
• Poxvirus DNA factories
• Lipid Membranes in Poxvirus Replication

Human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) are the most prevalent deadly chronic viral diseases. HIV is treated by small molecule inhibitors. HBV is treated by immunomodulation and small molecule inhibitors. HCV is currently treated primarily by immunomodulation but many small molecules are in clinical development. Although HIV is a retrovirus, HBV is a double-stranded DNA virus, and HCV is a single-stranded RNA virus, antiviral drug resistance complicates the development of drugs and the successful treatment of each of these viruses. Although their replication cycles, therapeutic targets, and evolutionary mechanisms are different, the fundamental approaches to identifying and characterizing HIV, HBV, and HCV drug resistance are similar. This review describes the evolution of HIV, HBV, and HCV within individuals and populations and the genetic mechanisms associated with drug resistance to each of the antiviral drug classes used for their treatment.

Comparison of the Mechanisms of Drug Resistance among HIV, Hepatitis B, and Hepatitis C. Viruses. 2010; 2(12):2696-2739. doi:10.3390/v2122696

Related:

• Update on HBV and HCV Therapy
• Can HIV infection be eradicated through use of potent antiviral agents?
• Plugging the holes in hepatitis C virus antiviral therapy

From the outside and within, we are constantly bombarded with a myriad of diverse microbial species. However, our bodies are equipped with an evolutionarily conserved innate immune defense system that allows us to thwart potential pathogens. Antimicrobial peptides (AMPs) are a unique and assorted group of molecules produced by living organisms of all types, considered to be part of the host innate immunity. These peptides demonstrate potent antimicrobial activity and are rapidly mobilized to neutralize a broad range of microbes, including viruses, bacteria, protozoa, and fungi. More significantly, the ability of these natural molecules to kill multidrug-resistant microorganisms has gained them considerable attention and clinical interest. With the growing microbial resistance to conventional antimicrobial agents, the need for unconventional therapeutic options has become urgent. This article provides an overview of AMPs, their biological functions, mechanism of action, and applicability as alternative therapeutic agents.

Presently, AMPs represent one of the most promising future strategies for combating infections and microbial drug resistance. This is evident by the increasing number of studies to which these peptides are subjected. As our need for new antimicrobials becomes more pressing, the question remains: can we develop novel drugs based on the design principles of primitive molecules?

Antimicrobial Peptides: Primeval Molecules or Future Drugs? (2010) PLoS Pathog 6(10): e1001067. doi:10.1371/journal.ppat.1001067

Related:

• Antimicrobial Peptides
• Antimicrobial Peptides: Primeval Molecules or Future Drugs?
• How to avoid getting killed