This new antibiotic is cause for celebration - and caution

In a grim week, reports of a new antibiotic [Ling et al., Nature] are a bright flash of urgently needed news.

The utility of existing antibiotics is being eroded alarmingly. Put simply, they provide an eloquent everyday demonstration of Darwin’s dictum of the ‘Survival of the Fittest’. As we use them to treat infections, we kill sensitive bacteria, but leave resistant ones to survive, either in the original infection or among the complex rainforest of the human gut – which contains more bacteria than the body contains human cells.

Over time, resistant bacteria accumulate among patients and antibiotics lose their potency. In the Forties, penicillin killed almost all Staphylococcus aureus – which commonly causes wound infection. By 1950, half of hospital S. aureus isolates were resistant. Now 90 per cent are.

We are also demanding more from our antibiotics, speeding the ratchet of evolutionary destruction. When they were introduced, we used them to treat classical infectious diseases – from syphilis to tuberculosis - to cure infected wounds, and to safeguard straightforward surgery in patients who were otherwise well. But by protecting patients from infection, antibiotics allowed a new sort of medicine to develop in which hitherto unthinkable procedures could be performed safely, including transplant surgery, immunosuppressive cancer treatments, intensive care, and special-care baby units. These are now taken for granted but, without antibiotics, would be untenable, for they tend to involve patients who are highly vulnerable to infection by “opportunistic" bacteria. Such bacteria are harmless in healthy people but lethal if they enter the blood of those with hugely weakened defences.

And it’s here, in high-tech medicine, that the fault line of resistance lies, for these opportunist bacteria are adept at acquiring and sharing resistance genes. What’s more, most are “Gram-negative”, meaning that they have a complex wall, which excludes many antibiotics that kill simpler Gram-positive bacteria such as S. aureus.

Antibiotic families have been eroded progressively in specialist medicine, with clinicians forced to move to routinely using drugs that previously were used as a last resort, notably carbapenems. And now, carbapenem resistance is proliferating. In Italy, two per cent of Klebsiella from bloodstream infections were carbapenem-resistant in 2008, 17 per cent were in 2010, and now resistance is at 30 per cent. Brazil and other Latin American countries appear on a similar trajectory. The situation is worse in India and parts of the Middle East, though surveillance is weak.

A HISTORY OF RESISTANCE

Once carbapenems are lost there is little left behind; clinicians must use an old and toxic antibiotic called colistin, combined with other sub-potent antibiotics. And colistin resistance is also now being seen.

The classic answer is to develop new antibiotics. But, after a Golden Age from the Forties to the Sixties, the flow of these has dwindled to a slow drip. The problem is three-fold. First it is scientifically hard to find new antibiotics, especially those that can get into Gram-negative bacteria. Secondly, with the best of intentions, the licensing process has become more complex, expensive and discouraging. Thirdly, antibiotics, which patients take briefly, are less commercially attractive than long-term treatments for chronic disease.

Unfortunately, big pharma wasted much time exploring a blind alley in the Nineties. Until then, antibiotics had either been sought from soil bacteria which made them naturally, or by tweaking existing molecules to evade resistance. As their processes seemed to be hitting the law of diminishing returns, companies moved to a new “scientific” strategy, facilitated by advances in molecular biology, of identifying targets inside the bacteria then making “designer antibiotics” to attack them. This approach failed completely. Companies found targets, but not the antibiotics to attack them. Or they found drugs that couldn’t enter the Gram-negative cell, or ones to which the target mutated resistance. These disappointments, along with the poor commercial potential led many companies to abandon the field of antibiotic discovery; others disappeared through mergers and acquisitions.

Gradually, though, as concerns with resistance increase, so too has the interest from big pharma. Roche, for example, has recently re-entered the field. Moreover, there is a growing raft of academic groups and start-ups seeking to improve older modes of antibiotic discovery.

Which brings us to Ling’s discovery. Many good antibiotic families – penicillin, streptomycin, tetracycline – come from soil fungi and bacteria and it has long been suspected that, if we could grow more types of bacteria from soil – or from exotic environments, such as deep oceans – then we might find new natural antibiotics.

Ling and colleagues found that they could isolate and grow individual soil bacteria – including types that can’t normally be grown in the laboratory – in soil itself, which supplied critical nutrients and minerals. Once the bacteria reached a critical mass they could be transferred to the lab and their cultivation continued. This simple and elegant methodology is their most important finding to my mind, for it opens a gateway to cultivating a wealth of potentially antibiotic-producing bacteria that have never been grown before.

The first new antibiotic that they’ve found by this approach ‘teixobactin’, from a bacterium called Eleftheria terrae, is less exciting to my mind, though it doesn’t look bad. Teixobactin killed ‘Gram-positive bacteria, such as S. aureus, in the laboratory, and cured experimental infection in mice. It also killed the tuberculosis bacterium, which is important because there is a real problem with resistant tuberculosis in the developing world. It was also difficult to select ‘teixobactin’ resistance.

So, what are my caveats? Well, I see three. First, teixobactin isn’t a potential panacea. It doesn’t kill the Gram-negative opportunists as it is too big to cross their complex cell wall. Secondly, scaling to commercial manufacture will be challenging, since the bacteria making the antibiotic are so difficult to grow. And, thirdly, it’s early days yet. As with any antibiotic, teixobactin now faces the long haul of clinical trials: Phase I to see what dose you can safely give the patient; Phase II to see if it cures infections and Phase III to compare its efficacy to that of “standard of care treatment”. That’s going to take five years and £500 million and these are numbers we must find ways to reduce (while not compromising safety) if we’re to keep ahead of bacteria, which can evolve far more swiftly and cheaply.

David Livermore is Professor of Medical Microbiology at University of East Anglia